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Cu(I) and Cu(II) Complexes Based on Lonidamine-Conjugated Ligands Designed to Promote Synergistic Antitumor Effects

Cite this: Inorg. Chem. 2022, 61, 12, 4919–4937
Publication Date (Web):March 14, 2022
https://doi.org/10.1021/acs.inorgchem.1c03658

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Abstract

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Bis(pyrazol-1-yl)- and bis(3,5-dimethylpyrazol-1-yl)-acetates were conjugated with the 2-hydroxyethylester and 2-aminoethylamide derivatives of the antineoplastic drug lonidamine to prepare Cu(I) and Cu(II) complexes that might act through synergistic mechanisms of action due to the presence of lonidamine and copper in the same chemical entity. Synchrotron radiation-based complementary techniques [X-ray photorlectron spectroscopy and near-edge X-ray absorption fine structure (NEXAFS)] were used to characterize the electronic and molecular structures of the complexes and the local structure around the copper ion (XAFS) in selected complexes. All complexes showed significant antitumor activity, proving to be more effective than the reference drug cisplatin in a panel of human tumor cell lines, and were able to overcome oxaliplatin and multidrug resistance. Noticeably, these Cu complexes appeared much more effective than cisplatin against 3D spheroids of pancreatic PSN-1 cancer cells; among these, PPh3-containing Cu(I) complex 15 appeared to be the most promising derivative. Mechanistic studies revealed that 15 induced cancer cell death by means of an apoptosis-alternative cell death.

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Synopsis

The antineoplastic drug lonidamine was conjugated with bis(pyrazolyl)acetates to obtain new Cu(I) and Cu(II) complexes, whose electronic and molecular structures were investigated using SR-XPS and XAS. All complexes showed significant antitumor activity in human tumor cell lines and were more effective than cisplatin against 3D spheroids of PSN-1 cancer cells.

Introduction

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Lonidamine (LND) is an antineoplastic drug able to sensitize tumors to radio-, chemo-, and photodynamic therapy. Although its mechanism of action is not completely clear yet, its use has been reported to affect the metabolic pathways of cancer cells by inhibiting mitochondrial respiration and glycolysis. (1−3) It has also been suggested that LND induces intracellular tumor acidification by inhibiting the efflux of l-lactic acid from cells mediated by monocarboxylate transporters and the mitochondrial uptake of pyruvate mediated by the mitochondrial pyruvate carrier. (4,5) Moreover, this drug induces a mitochondrial transmembrane potential disruption through a direct effect on the mitochondrial permeability transition pore. (6,7)
Although the antitumor activity of LND as a single agent is limited, this drug has great potential in increasing the efficacy of traditional chemotherapeutic agents, including cisplatin and other platinum-based drugs. (1,8−10) Platinum complexes conjugated with LND or its derivatives showed interesting antitumor activity profiles in vitro, with improved cytotoxic effects compared to that of cisplatin and other reference drugs. (11−13) In addition, a recent and promising approach concerned the preparation and biological study of gold nanoparticles conjugated with LND and aptamer AS1411 as effective cancer treatments. (14)
Cu(I) and Cu(II) complexes have received great attention for their both in vitro and in vivo unique properties. (15−27) Copper complexes and copper-based nanomedicines (28,29) are coming out as promising antitumor agents due to the elevated need for copper in cancer tissues compared to that in normal cells and its role as a limiting factor for multiple aspects of tumor progression, including angiogenesis, growth, and metastasis. (22,30−34) While tumor cells, avid of copper to fuel neovascularization in tumor progression, enrich their copper content, eventually causing copper overload and thus cell death, normal cells continue to adopt physiological mechanisms that regulate copper intracellular concentration. Somewhat reversing the anticancer strategy based on sequestration of copper to prevent establishment of the tumor blood supply, (35) tumor cells may represent a suitable, selective target for copper-based antitumor drugs. (36) Actually, anticancer copper-based drugs are endowed with improved selectivity toward tumor cells. Even if little information is available on the molecular basis for the mode of action of copper complexes, several molecular effectors and signalling pathways have emerged as suitable targets for copper complexes. (36,37)
In addition, endogenous metal ions are generally less toxic than nonendogenous ones toward normal cells, and for this reason, copper complexes might represent efficacious alternatives to Pt-based drugs. (34,36,38−42) Copper complexes show broader spectra of activities and lower toxicity, thereby providing the possibility of circumventing the problems encountered by platinum drugs, such as dose-limiting toxicity and inherent/acquired resistance. (43,44) Considering their reactivity to biomolecules other than DNA, there is increasing evidence that the mechanisms of action of copper complexes are markedly different from those of platinum drugs. (45,46) In this contest, some classes of copper complexes were found to exert an effective antiproliferative action by dysregulating mitochondrial function in cancer cells. (47)
To our knowledge, no copper complexes with LND derivatives have been reported in the literature to date. Therefore, the aim of this work was to functionalize LND with species able to coordinate metals in order to form Cu(I) and Cu(II) complexes potentially capable of exerting an anticancer activity through synergistic mechanisms of action.
For this purpose, LND was converted into 2-hydroxyethylester and 2-aminoethylamide derivatives LONES and LONAM, respectively, which were conjugated to bifunctional species bis(pyrazol-1-yl)acetic acid [HC(pz)2COOH] and bis(3,5-dimethyl-pyrazol-1-yl)acetic acid [HC(3,5-Me2pz)2COOH] to form heteroscorpionate ligands 1–4 (L1–L4, Scheme 1). HC(pz)2COOH and HC(3,5-Me2pz)2COOH were selected as coordinating agents for their κ3-NNO coordination properties of bis(azol-1-yl)methane (48) and for the presence of a carboxylic function suitable to be derivatized with the hydroxyl group of LONES or the primary amino group of LONAM. In addition, we have recently reported that copper complexes with heteroscorpionate ligands, obtained via conjugation with nitroimidazole, glucosamine, and a noncompetitive NMDA receptor antagonist, showed cytotoxic activity toward a panel of several human tumor cell lines. (49−52)

Scheme 1

Scheme 1. Synthesis of Ligands 1–4 and Complexes 5–16; Reagents and Conditions: (a) HOCH2CH2OH, H2SO4, 85 °C, 1 h; (b) H2NCH2CH2NH2, CDI, THF, 18 h; (c) HC(pz)2COOH or HC(3,5-Me2pz)2COOH, DMAP, EDCI·HCl,16 h; (d) HC(pz)2COOH or HC(3,5-Me2pz)2COOH, HOBT, EDCI·HCl, DMF, 16 h; (e) PTA, Cu(CH3CN)4PF6, CH3CN, Overnight; (f) PPh3, Cu(CH3CN)4PF6, CH3CN, Overnight; and (g) CuCl2·2H2O, CH3CN, 24 h
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Ligands 1–4 were used for the preparation of Cu(I) and Cu(II) complexes 5–16 (Scheme 1) that might act through synergistic mechanisms of action due to the presence of LND and copper in the same chemical entity. Concerning the Cu(I) complexes, to stabilize copper in the +1 oxidation state, lipophilic triphenylphosphine (PPh3) and hydrophilic 1,3,5-triaza-7-phosphaadamantane (PTA) were selected as coligands in order to confer different solubility properties to the corresponding complexes.
The molecular structure of selected coordination compounds was investigated in the solid state by means of synchrotron radiation-induced X-ray photoelectron spectroscopy (SR-XPS), near-edge X-ray absorption fine structure (NEXAFS), and X-ray absorption spectroscopy (XAS); the multitechnique approach allowed us to properly define the coordination geometry around the copper ion, as well as to ascertain the molecular structural stability of the ligands upon interaction with the metal. (53)
The new complexes 5–16, the corresponding uncoordinated ligands 1–4, and LND were investigated for their cytotoxic potential on a panel of human cancer cell lines, derived from different solid tumors, by means of both 2D and 3D cell viability studies. The cell panel also includes cancer cells selected for their resistance to oxaliplatin or multidrug resistant (MDR) cells. Furthermore, mechanistic studies were performed in order to elucidate the multimodal mechanistic effect of the new Cu(I) and Cu(II) species.

Results and Discussion

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Synthesis and Characterization

Starting materials LONES and LONAM and ligands L1, L2, L3, and L4 were prepared according to the procedure reported in Scheme 1. In particular, the reaction between LND and ethylene glycol in the presence of sulfuric acid led to intermediate LONES, which was treated with acids HC(pz)2COOH and HC(3,5-Me2pz)2COOH (54,55) in the presence of 3-(ethyliminomethylideneamino)-N,N-dimethyl-propane-1-amine hydrochloride (EDCI·HCl) and N,N-dimethylaminopyridine (DMAP) to give ligands L1 (1) and L2 (2), respectively. Treatment of LND with ethylenediamine in the presence of carbonyldiimidazole (CDI) led to intermediate LONAM, which reacted with HC(pz)2COOH or HC(3,5-Me2pz)2COOH in the presence of EDCI·HCl and 1-hydroxybenzotriazole (HOBT) to give ligands L3 (3) and L4 (4), respectively. After separation and purification via column chromatography, ligands 1–4 were obtained in a reasonable yield and purity. They are soluble in CHCl3, CH2Cl2, dimethyl sulfoxide (DMSO), and CH3OH but insoluble in water. Ligands 1–3 are also soluble in CH3CN. The infrared (IR) spectra obtained for solid samples of ligands 1–4 showed all the bands expected for these heteroscorpionate ligands. The 1H nuclear magnetic resistance (NMR) spectra, recorded in CDCl3 and in DMSO-d6 solution at room temperature, show all the expected signals for the bioconjugated ligands with a single set of resonances for the pyrazole rings, indicating that the pyrazole protons are equivalents. The elemental analyses confirm the stoichiometry and the purity of the products in the solid state.
Cu(I) complexes [(PTA)2Cu(L1)]PF6 (5), [(PTA)2Cu(L3)]PF6 (8), [(PTA)2Cu(L2)]PF6 (11), and [(PTA)2Cu(L4)]PF6 (14) were prepared via the reaction of PTA, Cu(CH3CN)4PF6, and ligands L1, L3, L2, and L4, respectively (Scheme 1), following a one-pot synthesis with CH3CN as the solvent. Analogously, Cu(I) complexes [(PPh3)2Cu(L1)]PF6 (6), [(PPh3)2Cu(L3)]PF6 (9), [(PPh3)2Cu(L2)]PF6 (12), and [(PPh3)2Cu(L4)]PF6 (15) were prepared via the reaction of PPh3, Cu(CH3CN)4PF6, and the related ligands (Scheme 1). All the compounds are soluble in CH3CN and DMSO; the complexes with PPh3 coligands (6, 9, 12, and 15) are also soluble in CHCl3; complexes 6, 9, 12, and 14 are soluble in methanol; complex 15 is soluble in ethanol; while complexes 8, 9, and 11 are soluble in acetone. The IR spectra obtained for solid samples of the Cu(I) complexes show all the expected bands for the bioconjugated ligands and the phosphane coligands. The absorptions due to the C═O stretching of the ester groups for complexes 5, 6, 11, and 12 do not significantly vary with respect to the same absorptions of the carbonyl groups detectable in the spectra of the free ligands. The absorptions due to the C═O stretching of the amide groups for 8, 9, 14, and 15 are slightly shifted at lower frequencies with respect to those of the free ligands. The 1H NMR spectra of the Cu(I) complexes, recorded in DMSO-d6 solution at room temperature, showed a single set of resonances for the pyrazole rings, indicating that the pyrazole protons are equivalents, with a slight shift due to the coordination to the metal center. A significant shift to higher frequencies of the N–H signals is detected only for compounds 14 (δ 8.43 and 9.07 ppm) and 15 (δ 8.38 and 9.35 ppm) probably due to a secondary interaction between the hydrogen atoms and the copper center. The PTA and PPh3 coligands show a characteristic series of peaks at δ 4.04–4.73 and 7.20–7.80 ppm, respectively, with an integration, with respect to the ligand peaks, that confirms the 1:2 stoichiometric ratio between the ligand and the phosphane coligands. The room-temperature 31P{H} NMR spectra of the Cu(I) complexes, recorded in DMSO-d6 and CD3CN solution at room temperature, give singlets shifted downfield with respect to the value of the free phosphanes PPh3 and PTA. The characteristic septet centered at about δ −144 ppm is due to the presence of the PF6– counterion. The electrospray ionization mass spectroscopy (ESI-MS) studies, performed by dissolving the Cu(I) complexes in CH3CN and recording the spectra in the positive- and negative-ion modes, confirm the formation of the PTA and PPh3 complexes and the presence of hexafluorophosphate as counterions.
Cu(II) complexes [(L1)CuCl2] (7), [(L3)CuCl2] (10), [(L2)CuCl2] (13), and [(L4)CuCl2] (16) were prepared via the reaction of CuCl2·2H2O with ligands L1, L3, L2, and L4, respectively, in acetonitrile solution for 7 and 13 and in methanol solution for 10 and 16 at room temperature (Scheme 1). All the compounds are soluble in DMSO; complexes 7 and 13 are soluble in CH3OH, CHCl3, and CH3CN; complexes 10 and 16 are slightly soluble in CH3CN; complex 16 is soluble in CHCl3; and complexes 13 and 16 are soluble in CH2Cl2. The IR spectra obtained for solid samples show all the expected bands for the bioconjugated ligands. The strong absorptions due to the C═O stretching of the ester and amide groups do not significantly vary with respect to the absorptions detectable for the free ligands. These data indicate that the carbonyl groups are not involved in the coordination of the metal: the copper center results in a tetracoordinated environment with the ligand chelating in a bidentate fashion and the other two positions being occupied by the chlorides. The ESI-MS studies, conducted by dissolving the Cu(II) complexes in CH3CN and recording the spectra in the positive- and negative-ion modes, confirm the formation of the complexes and the presence of the chlorides as counterions.

Investigation of the Molecular and Electronic Structures

Synchrotron Radiation-Induced X-ray Photoelectron Spectroscopy

The electronic and molecular structures of coordination compounds 10, 15, and 16, in comparison with those of ligand 4, were probed using SR-XPS. SR-XPS spectra were collected at C 1s, N 1s, O 1s, Cl 2p, P 2p (for 15), F 1s (for 15), and Cu 2p core levels; the detailed data analysis results [binding energy (BE), full width at half maximum (FWHM), and assignments], confirming the proposed molecular structures for the complexes and the stability of the ligand 4 molecular structure upon coordination to copper, are collected in the Supporting Information (Table S1). In the following, the most interesting signals are described and compared for the three analyzed samples, considered representative of Cu(II) and Cu(I) coordination compounds.
The C 1s signal can always be resolved using curve fitting analysis into several components corresponding to the different C atoms in the proposed molecular structure. More in detail, in the order of increasing BE, the contributions are assigned as follows: aromatic and aliphatic C–C carbons (BE = 284.7 eV), C–N carbons of the pyrazole-like rings (BE = 286.6 eV), C═O carbonyls of amide groups and imine-like C═N groups (BE = 288.0 eV), −COOH impurities always found on the surface of samples deposited in air (BE = 289.3 eV), and C–Cl groups (BE = 291.5 eV). C 1s spectra of ligand 4 and complexes 10 and 15 are reported in Figure 1A–C.

Figure 1

Figure 1. C 1s spectra of ligand 4 (A), Cu(II) complex 10 (B), and Cu(I) complex 15 (C) and N 1s spectra of 4 (D) and coordination compounds 10 (E) and 15 (F).

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N 1s spectra of ligand 4 and complexes 10 and 15 are reported in Figure 1D–F, respectively. For 4, a couple of main signals can be detected at 399.5 and 401.0 eV BEs, indicative for the two kinds of nitrogens of the pyrazole rings, that is, amine-like and imine-like N atoms, respectively. (56) Amide-like N atoms are found at a BE value very close to that of the amine-like N atoms and cannot be resolved due to the experimental resolution (0.6 eV). As for the coordination compounds, it is expected that only the amine-like contribution appears when the two nitrogen atoms coordinate with a metal ion, as reported in the literature for heterocycles coordinating metal ions (e.g., porphyrins or phthalocyanines). (57−59) In excellent agreement with this prediction, in complexes 10, 15 (Figure 1E,F, respectively), and 16, a single N 1s component at about 400.0 eV, attributed to the symmetrized nitrogen atoms coordinating to copper ions (and to the indistinguishable amide-like N), can be observed. Cl 2p BE values observed for both ligand 4 and the three coordination compounds 10, 15, and 16 (Cl 2p3/2 BE = 200 eV) are compatible with chlorine atoms covalently bonded to carbon in organic molecules. (60) In addition, in Cl 2p spectra of 10 and 16, a contribution of slightly higher intensity at a lower BE (198 eV BE) can be observed, as expected for chlorine atoms bonded to Cu(II) ions in the coordination compounds. (60,61)
Cu 2p spectra collected for copper complexes 10 and 15 are reported in Figure S1 in the Supporting Information; both Cu 2p spectra collected for complexes 10 and 16 show a spin–orbit pair with the Cu 2p3/2 component centered at 936 eV, indicative of Cu(II) ions in coordination compounds, (60) in excellent agreement with analogous systems. (59) On the other hand, the Cu 2p spectrum collected on complex 15 has the Cu 2p3/2 spin–orbit component centered at a 932.0 eV BE, as expected for Cu(I) ions in coordination compounds. (60)

NEXAFS Data Analysis Results

NEXAFS spectroscopy measurements were carried out at C and N K-edges on ligand 4 and on coordination compounds 10 and 16, with the aim to obtain further information about the influence of the metal coordination on the electronic structure of the ligand. Experimental spectra of the C K-edge and N K-edge of 4, 10, and 16 samples are reported in Figure 2. They were collected at the grazing incidence of the polarized photon beam with respect to the sample surface; no angular dependence was observed on the NEXAFS spectra of the investigated compounds when the incidence angle of the impinging radiation was changed from grazing to magic and normal, indicating the absence of a preferential orientation of the investigated molecules on the sample surface.

Figure 2

Figure 2. C K-edge (left) and N K-edge (right) NEXAFS spectra of ligand 4 and Cu(II) complexes 10 and 16.

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According to the literature, (59,62−65) peak positions and assignments of the main features detected in the C and N K-edge spectra of the analyzed samples are also shown in Table 1.
Table 1. NEXAFS: Peak Position (eV) and Relative Assignment of the Main Features Appearing in the C and N K-Edge NEXAFS Spectra of Samples 4, 10, and 16
sample41016assignment
C K-edge284.7285.1284.8πC═C*
 286.0286.2286.4πC═N*
 287.6287.8287.8σC–H*
 288.4288.4288.4πC═O*
 293.4294.3291.5σC–C*
 301.5303.5299.0σC═N*
N K-edge396.1396.1396.1 
 397.5397.9397.9π1*
 399.4399.4399.4π2*
 404.9403.7403.7σC═N*
 411.0411.0411.0σC–N*
For the C K-edge spectra, the energy scale is referenced to the πC═O* transition of the amide function in the side chain of LND, (62,65) while for the N K-edge spectra, the energy scale is referenced to the π2* transition of the pyrazole ring. (59,63,64)
The C K-edge spectra present the expected πC═C* and πC═N* features of the pyrazole ring and the πC═O* feature related to the amide group at 288.4 eV. It can be noticed (Table 1) that the first two peaks lie at lower energy in 4 and that the πC═N* peak is attenuated in Cu complexes 10 and 16 with respect to that in ligand 4. These effects could be related to the Cu complexation of the pyrazole nitrogens.
All the samples exhibit a σC–H* resonance originated from the presence of the aliphatic chains. Above the edge, two large features σC–C* and σC═N* can be observed.
The N K-edge spectra show the N 1s → π* transitions (π1* and π2*) originating from two distinct nitrogen atoms. As shown in Table 1, the energy of the π1* peak is higher for Cu complexes 10 and 16 than for ligand 4: this effect might be further evidence of the complexation with copper. The weak feature detected at 296.1 eV for all the analyzed samples is probably related to impurities on the beamline mirrors.

XAFS Data Analysis Results

X-ray absorption data collected at the Cu K-edge on selected complexes 10, 15, and 16 were analyzed with the aim of understanding the average local coordination chemistry and electronic structure around Cu. The main near-edge features (XANES) originate from the absorber valence state (edge position) and coordination geometry (edge shape). (66) The Cu K-edge normalized XANES spectra measured on complexes 10, 15, and 16 are presented in Figure 3, together with those measured on Cu metal foil and reference Cu oxides, for the sake of comparison. The edge energies of complexes 10 and 16 match the edge energy of the pure CuO reference compound, in accordance to the Cu(II) valence state in these complexes. (59) A roughly planar geometry could be assumed for sample 10 due to the close similarity with the XANES spectrum of the glycine complex reported in the literature. (67) The XANES spectrum measured from complex 16 (Figure 3) depicts a higher white line (around 8995 eV) with respect to complex 10 and attenuation of the pre-edge shoulder, this behavior being compatible with the Cu coordination geometry changing from square planar in complex 10 to nearly octahedral in complex 16. The complex 15 edge position matches the edge energy measured on the pure Cu2O reference compound, confirming the Cu(I) valence state. The pre-edge peak we found at 4 eV above the Cu0 edge is related to the copper coordination geometry and type of neighbors. Its amplitude is expected to be the highest (around 1) for the Cu(I) bidentate coordination, (66) while it decreases upon increasing the Cu(I) coordination number and/or reducing the Cu(I) site symmetry. (68,69) We found the pre-edge peak amplitude of around 0.52 of the edge jump consistent with 3- or 4-coordinated Cu. The squeezing of the structural oscillations in the XANES region, with respect to the Cu2O spectrum, suggests averagely longer neighbor distances in complex 15. Further details about the local structure are obtained from the quantitative analysis of the EXAFS region.

Figure 3

Figure 3. Cu K-edge normalized XANES spectra measured on complexes and reference compounds, shifted for the sake of clarity. Edge energies of Cu(II) complexes 10 and 16 match the edge energy of the CuO reference compound. The edge energy of Cu(I) complex 15 matches the edge energy of Cu2O.

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Looking at the k2-weighted EXAFS signal in the k space and at its Fourier transform (FT) in the real space, remarkable differences are evident among the samples (Figure 4). In particular, looking at complexes 10 and 16, the k2χ(k) signal presents a prominent first oscillation in sample 16, while in sample 10, two oscillations of equal and lower intensity are visible. Moreover, from the first oscillation onward, the signals become partially out of phase. Such a different behavior corresponds to differences in the real space for the FT spectra. Noticeably, the modulus and imaginary part of the FT depict very similar shapes (Figure 4, dashed lines) except around 2 Å (Figure 4, red arrow), where a lack of the structural signal is found in the sample 16 data with respect to the sample 10 data. This behavior may point out some antiphase structural signal originating from a different neighbor arrangement around Cu in the two complexes. (70) Noticeably, complex 16 has two CH3 substituents that may provide such an additional coordination shell, in agreement with the XANES features suggesting the nearly octahedral coordination. Moreover, such a different coordination seems to promote greater rigidity of the structure, providing larger next neighbor signals in the next neighbor region (highlighted by dashed lines in Figure 4B). Looking at the weaker k2χ(k) signal of complex 15, it is evident that the local structure around Cu(I) is definitively more disordered than those of Cu(II) complexes.

Figure 4

Figure 4. (A) Cu K-edge EXAFS data analysis of complexes 10, 15, and 16 are reported. At the top, the experimental k2χexp(k) (dots) and best fit curves k2χfit(k) (black lines) are presented (vertically shifted for clarity). The middle curves (orange) represent the partial contributions used in the analysis of Cu(II) complex 10 (vertically shifted for clarity) for the sake of the example, and the lowest curve (gray) is the best fit residual k2(χfit – χth). (B) Corresponding FT moduli are shown for experimental k2 weighted EXAFS data (dots) and the best fit (black lines). The FT imaginary (Imm-FT) part of the experimental spectrum, best fit, and partial contributions are shown for complex 10 for the sake of an example. The dashed lines highlight in-phase Imm-FT oscillations for Cu–N and Cu–Cl contributions in Cu(II) complexes 10 and 16. The red arrow points out the structural signal lack in the region of the Cu–Cl shell (red dashed line) likely due to some antiphase structural signals. (C) Local structure around Cu is shown to highlight the neighbor shells involved in the analysis, being R = H (complex 10) or R = CH3 (complex 16) (see Scheme 1) and Y = Cl [Cu(II) complexes 10 and 16] and Y = P [Cu(I) complex 15].

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Quantitative details were obtained from EXAFS data fitting (see the Supporting Information for details). The distances and mean square relative displacement (MSRD) σ2 obtained from the refinement are reported in Table 2 for single scattering (SS) contributions. In complex 10, the distances demonstrate a good agreement with the expected molecular structure. The Cu–N nearest neighbor shell is found at 1.96 Å, and Cl is at 2.23 Å from Cu(II). The complex 16 EXAFS data analysis demonstrates the octahedral distorted geometry for Cu in complex 16 with two closer Cu–N and Cu–CR nearest neighbor shells and a third longer Cu–Cl shell, and the Cu–CR link would likely originate from the CH3 residue. Noticeably, the bimodal Cu–C/N(2) shell resulting in a shorter shell at around 2.9 Å and a long one at around 3.3 Å is consistent with the tilting of pyrazole rings.
Table 2. Best Fit Results for Cu K-Edge XAFS Data Analysis of Complexes 10, 15, and 16a
  sample 10 Cu(II)sample 16 Cu(II)sample 15 Cu(I)
 NR (Å)σ2 × 102 (Å2)R (Å)σ2 × 102 (Å2)R (Å)σ2 × 102 (Å2)
Cu–N21.959(5)0.68(5)1.967(7)0.24(3)2.001(3)3.2(2)
Cu–CR2  1.89(2)1.62(2)  
Cu–Cl(P)22.23(1)0.64(4)2.21(2)2.3(2)2.16(1)0.69(3)
Cu–C/N(2)42.97(3)0.86(2)2.85(2)0.75(3)2.92(2)1.3(2)
    3.35(3)0.45(2)  
Cu–CPh39    3.29(3)1.4(5)
Cu–C(2) (SS + MS)44.08(3) 4.40(3)0.84.05(8)2.1
a

The Cu–CR shell originates from the carbons of R = CH3 groups of the pyrazoles; Cu–CPh3 originates from the C atoms of phenyl rings bonded to P of PPh3. The multiplicity numbers (N) are constrained to the structural model, and interatomic distances [R (Å)] and the MSRD (σ2) parameters are shown. Standard uncertainties on the last digit are reported in parentheses.

In complex 15, the Cu–N nearest neighbor distance is slightly longer with respect to the other complexes and largely more disordered. We found a significatively better fit using 2N + 2P neighbor shells with respect to 1N + 2P or 2N + 1P, but the quite large σ2 found for the Cu–N suggests more loosely bound Cu(I) in complex 15 with respect to complexes 10 and 16, likely related to the lower electronegativity of Cu(I). In summary, the Cu oxidation and the local structure around Cu obtained via XAFS is consistent with the expected complex structure; the Cu(I) local structure appears more distorted likely due to the more loosely bound neighbor.

Stability Studies

The stability of the new complexes in 0.5% DMSO/RPMI cell culture medium was also evaluated using UV–vis spectroscopy. Changes observed in the UV–vis spectra of the complexes over 24 h were insignificant or only minimal for complexes with L3 and L4 ligands, indicating that these complexes are stable under physiological conditions (Figure S2 in the Supporting Information). On the contrary, for complexes with L1 and L2 ligands, a more evident change in the UV–vis spectrum was detected.

Cytotoxicity Studies

The newly developed complexes 5–16, the corresponding uncoordinated ligands 1–4, and their precursors were evaluated for their ability to promote cell death in a panel of human cancer cell lines derived from solid tumors (2008 ovarian, HCT-15 colon, PSN-1 pancreatic, A431 cervical, and H157 lung carcinoma cells). The cytotoxicity parameters, expressed in terms of IC50 and obtained after 72 h of drug exposure using a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, are reported in Table 3. For comparison purposes, the cytotoxicity of cisplatin was assessed under the same experimental conditions.
Table 3. Cytotoxic Activity of LND, LONES, LONAM, 1–16, and Cisplatina
 IC50 (μM) ± S.D.
compound2008HCT-15PSN-1H157A431
LND24.9 ± 3.3>2524.6 ± 2.9>25>25
LONES>25>2521.3 ± 2.4>25>25
LONAM18.2 ± 0.9>25>25>25>25
1 (L1)11.70 ± 0.0213.4 ± 5.314.3 ± 3.816.8 ± 2.412.5 ± 2.1
2 (L2)21.3 ± 3.56.2 ± 0.52.7 ± 0.35.2 ± 0.73.2 ± 0.2
3 (L3)7.9 ± 2.24.7 ± 1.63.1 ± 0.95.6 ± 1.43.7 ± 1.6
4 (L4)2.9 ± 1.11.9 ± 1.01.5 ± 0.51.3 ± 0.61.4 ± 0.5
5 [(PTA)2Cu(L1)][PF6]2.4 ± 0.92.5 ± 0.51.2 ± 0.11.3 ± 0.50.4 ± 0.1
6 [(PPh3)2Cu(L1)][PF6]2.2 ± 0.81.7 ± 0.61.4 ± 0.11.30 ± 0.030.6 ± 0.3
7 [(L1)CuCl2]2.8 ± 0.91.6 ± 0.41.6 ± 0.40.6 ± 0.20.70 ± 0.02
8 [(PTA)2Cu(L3)]PF60.8 ± 0.30.4 ± 0.10.6 ± 0.20.6 ± 0.10.60 ± 0.01
9 [(PPh3)2Cu(L3)]PF61.1 ± 0.30.30 ± 0.010.5 ± 0.10.40 ± 0.011.0 ± 0.2
10 [(L3)CuCl2]1.20 ± 0.020.2 ± 0.10.5 ± 0.20.5 ± 0.21.6 ± 0.8
11 [(PTA)2Cu(L2)][PF6]2.2 ± 0.92.2 ± 0.41.0 ± 0.40.5 ± 0.20.6 ± 0.1
12 [(PPh3)2Cu(L2)][PF6]1.4 ± 0.13.4 ± 0.10.6 ± 0.11.2 ± 0.20.7 ± 0.1
13 [(L2)CuCl2]1.3 ± 0.24.7 ± 0.90.5 ± 0.11.0 ± 0.21.5 ± 0.6
14 [(PTA)2Cu(L4)]PF60.7 ± 0.20.3 ± 0.11.0 ± 0.30.900 ± 0.0010.5 ± 0.2
15 [(PPh3)2Cu(L4)]PF60.6 ± 0.10.3 ± 0.10.6 ± 0.10.3 ± 0.10.4 ± 0.2
16 [(L4)CuCl2]0.8 ± 0.80.2 ± 0.11.6 ± 0.20.60 ± 0.021.00 ± 0.01
cisplatin2.2 ± 1.015.3 ± 2.612.1 ± 2.82.1 ± 0.82.1 ± 0.9
a

Cells (3–8 × 103 mL–1) were treated for 72 h with the tested compounds. Cell viability was measured by means of an MTT test. The IC50 values were calculated using a 4-PL logistic model (P < 0.05). S.D. = standard deviation.

LND and ligand precursors LONAM and LONES did not induce a significant reduction of cell viability (the IC50 values were greater than 25 μM). Uncoordinated ligands 1–4 possessed a moderate cytotoxic potency that was, however, on average, 3 to 10 times lower than that of the corresponding metal complexes. Actually, all tested copper complexes showed a promising cytotoxic potential, with IC50 values in the low or submicromolar range toward all the human cancer cell lines belonging to the in-house panel, and proved to be more effective than the reference chemotherapeutic drug cisplatin. These results suggest that both LND and copper might contribute to the potent antitumor activity of these complexes.
In general, L1 and L2 derivatives were on average less effective than the corresponding L3 and L4 complexes, and among the series, no significant differences in terms of in vitro antitumor activities were detected for Cu(I) and Cu(II) complexes. It is important to note that complexes with L1 and L2 ligands were less stable in physiological media compared with complexes bearing L3 and L4. Hence, their lower cytotoxic effectiveness could be attributed, at least in part, to their instability in physiological conditions. Among all, complex 15 was the most effective derivative, eliciting, on average, IC50 values about 16 times lower than those detected with cisplatin. On the contrary, compound 5 was the weakest among the series, with a cytotoxic potency that was, however, more than 4 times higher than that of cisplatin.
Considering the very promising antiproliferative effects and keeping in mind that drug resistance represents a key determinant for the variable efficacy of anticancer therapy, we also assessed the ability of the newly developed Cu(I) and Cu(II) complexes to bypass the acquired drug resistance. In particular, complexes were evaluated for their antiproliferative activity against some cancer cell lines selected for sensitivity/resistance to oxaliplatin or MDR cells, namely, LoVo, LoVo-OXP, and LoVo MDR human colon cancer cells.
As previously reported, LoVo OXP cells (derived from LoVo cells grown in the presence of increasing concentrations of oxaliplatin) were about 13-fold more resistant to oxaliplatin than parental cells. (23) The main molecular mechanisms involved in oxaliplatin resistance appear to depend upon (i) the decreased cellular accumulation, which is thought to be related to a greater activity of the ATP7B exporter rather than the activity of P-glycoprotein (P-gp) and multidrug resistance protein 1 (MRP1), and (ii) the more efficient repair of oxaliplatin-induced DNA damage via nucleotide excision repair (NER). (71) Conversely, in human colon LoVo MDR cancer cells, the resistance to doxorubicin, a drug belonging to the MDR spectrum, is associated with an overexpression of drug transporters, such as the 170 kDa P-gp. (72)
Table 4 shows the degree of resistance in terms of the resistant factor (RF), which is defined as the ratio between IC50 (obtained using an MTT assay after 72 h of drug exposure) calculated for the resistant cells and those arising from the sensitive ones (Table 4).
Table 4. Cross-Resistance Profile of Complexes 5–16, Oxaliplatin, and Doxorubicina
 IC50 (μM) ± S.D.
compoundLoVoLoVo OXPRFLoVo MDRRF
5 [(PTA)2Cu(L1)][PF6]2.4 ± 0.31.8 ± 0.50.81.6 ± 0.70.7
6 [(PPh3)2Cu(L1)][PF6]1.4 ± 0.41.1 ± 0.30.81.2 ± 0.40.9
7 [(L1)CuCl2]1.8 ± 0.51.7 ± 0.60.91.0 ± 0.40.6
8 [(PTA)2Cu(L3)]PF60.9 ± 0.10.7 ± 0.20.80.7 ± 0.30.9
9 [(PPh3)2Cu(L3)]PF60.20 ± 0.050.30 ± 0.041.50.10 ± 0.030.5
10 [(L3)CuCl2]0.6 ± 0.10.7 ± 0.11.00.8 ± 0.21.3
11 [(PTA)2Cu(L2)][PF6]2.8 ± 0.72.2 ± 0.90.82.5 ± 0.40.9
12 [(PPh3)2Cu(L2)][PF6]2.2 ± 0.41.6 ± 0.30.71.7 ± 0.60.8
13 [(L2)CuCl2]2.8 ± 0.72.1 ± 0.60.82.0 ± 0.50.7
14 [(PTA)2Cu(L4)]PF60.4 ± 0.10.7 ± 0.11.80.7 ± 0.21.0
15 [(PPh3)2Cu(L4)]PF60.20 ± 0.020.20 ± 0.031.00.10 ± 0.010.5
16 [(L4)CuCl2]0.8 ± 0.10.9 ± 0.31.11.1 ± 0.31.4
oxaliplatin1.5 ± 0.619.6 ± 1.913.1  
doxorubicin1.1 ± 0.5  19.4 ± 2.217.4
a

Cells (5 × 103 mL–1) were treated for 72 h with the tested compounds. Cell viability was measured by means of an MTT test. IC50 values were calculated using the 4-PL logistic model (P < 0.05). S.D. = standard deviation. RF = IC50 (resistant cells)/IC50 (wild-type cells).

All complexes were equally effective against sensitive (LoVo) and resistant (LoVo-OXP) colon cancer cells and possessed RFs much lower than that of doxorubicin, thus attesting their ability to overcome the oxaliplatin resistance and the MDR phenomenon and not acting as P-gp substrates.
Clearly, such results make these complexes promising for further biological studies aiming at an application in solid tumors refractory to platinum drug treatment.
In an attempt to better appreciate the antitumor potential of the new Cu(I) and Cu(II) complexes containing the LND-conjugated ligands, we compared their cytotoxic profiles with those of similarly unconjugated or differently conjugated (pyrazolyl)acetate complexes that we had previously characterized. (49,52,73,74) No significant differences in terms of antiproliferative activity and overcoming drug resistance have been detected. The calculated IC50 values, both in sensitive and resistant cancer cells, were always in the very low or submicromolar range. The newly developed copper complexes were also screened against 3D spheroids of pancreatic PSN-1 cancer cells to further evaluate their anticancer potential. Actually, 3D cell cultures possess several features that more closely mimic the in vivo tumor architecture and physiology, being consequently potentially more predictive for in vivo effectiveness. (75) The cancer spheroids were treated with the tested complexes for 72 h, and cell viability was assessed by means of the acid phosphatase (APH) assay (Table 5). Notably, all complexes were much more effective than cisplatin against the 3D model. Similarly to 2D studies, L1 and L2 derivatives were less effective than the corresponding L3 and L4 complexes. Differently from cytotoxicity studies performed on 2D cell cultures, in 3D models, Cu(I) complexes with PPh3 ligands proved to be much more effective than Cu(II) derivatives. These results could be related to the more lipophilic character of PPh3-containing Cu(I) complexes, which makes them more effective at penetrating across the entire spheroid domain, including the inner core. Complex 15 again emerged as the most promising derivative, with an IC50 value roughly 12-fold better than that of cisplatin, and complex 5 as the less effective derivative of the series.
Table 5. Cytotoxicity toward Pancreatic PSN-1 Cancer Cell Spheroids of Complexes 5–16 and Cisplatina
 IC50 (μM) ± S.D.
compoundPSN-1
5 [(PTA)2Cu(L1)][PF6]40.4 ± 2.0
6 [(PPh3)2Cu(L1)][PF6]8.3 ± 1.2
7 [(L1)CuCl2]33.0 ± 3.0
8 [(PTA)2Cu(L3)]PF611.6 ± 1.6
9 [(PPh3)2Cu(L3)]PF66.8 ± 0.4
10 [(L3)CuCl2]7.6 ± 0.3
11 [(PTA)2Cu(L2)][PF6]31.9 ± 4.0
12 [(PPh3)2Cu(L2)][PF6]22.0 ± 2.1
13 [(L2)CuCl2]34.0 ± 2.1
14 [(PTA)2Cu(L4)]PF66.6 ± 0.5
15 [(PPh3)2Cu(L4)]PF64.5 ± 0.4
16 [(L4)CuCl2]13.7 ± 3.7
cisplatin52.6 ± 4.9
a

Cancer cell spheroids (2.5 × 103 cells/well) were treated for 72 h with the tested compounds. Cell viability was evaluated by means of the APH test. IC50 values were calculated from the dose–response curves obtained using the 4-PL logistic model (P < 0.05). S.D. = standard deviation.

As compound 15 emerged as the most promising derivative from cytotoxicity studies in both 2D and 3D models, it was selected for uptake and mechanistic studies. Derivatives 14 and 16, bearing the same ligand but a different coligand or a different Cu oxidation state, were included in these studies for useful comparison.

Cellular Uptake

As stated before, copper accumulation in cancer cells is one of the most important factors affecting copper complex cytotoxicity. In an attempt to correlate cytotoxic activity with cellular accumulation, copper content was evaluated in PSN-1 cells treated for 24 or 36 h with 1 μM of complexes 14–16. The intracellular copper amount was quantified by means of graphite furnace atomic absorption spectrometry (GF-AAS) analysis, and the results, expressed as metal parts per billion per 106 cells, are shown in Figure 5.

Figure 5

Figure 5. Intracellular copper content after treatment with compounds 14–16. PSN-1 cells were treated for 24 or 36 h with 1 μM copper complexes, and the intracellular copper amount was estimated using GF-AAS analysis. Error bars indicate the standard deviation. *P < 0.1 and **P < 0.01 compared with the control.

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Although to a different extent, all three copper complexes accumulated into cancer cells. Notably, the intracellular Cu levels follow the trend 15 > 14 > 16 after 24 h, thus suggesting that Cu(I) complexes are more effective in crossing the cancer cell membrane with respect to the Cu(II) derivative. Interestingly, in the case of the Cu(II) complex 16, the intracellular copper levels significantly increased with exposure time, whereas Cu(I) complexes 14 and 15 seemed to accumulate in a time-independent manner. These results might suggest the involvement of different internalization mechanisms for Cu(I) and Cu(II) complexes, whose electronic and molecular structures have been confirmed using XPS and XAS analysis. Moreover, by comparing uptake and cytotoxicity data in human pancreatic PSN-1 cancer cells, a direct correlation between cellular accumulation and cytotoxic potency can be highlighted.

Mechanistic Studies

Copper complexes have been regarded as redox active modulators as they may catalyze hydrogen peroxide in the form of Fenton-like reactions inside the cell to produce reactive oxygen species (ROS), thus altering the cellular redox homeostasis and driving cells toward oxidative stress. (76) In addition, it has previously been reported that LND acts as an antitumor drug by inhibiting both mitochondrial respiration and glycolysis, thus shifting cultured cells to a more oxidized redox state. (77) Moreover, some classes of copper complexes were found to exert an effective antiproliferative action by dysregulating the mitochondrial function in cancer cells. (47)
On these bases, we evaluated the ability of 14–16 to alter cellular redox homeostasis, in terms of total cellular sulfhydryl content, ROS production, and perturbation of the mitochondrial membrane potential in PSN-1 cells (Figure 6). For compounds 15 and 16, SR-XPS data analysis provided information about the electronic and molecular structures, evidencing the molecular structural stability for both Cu(I) and Cu(II) complexes and confirming the expected oxidation states.

Figure 6

Figure 6. (A) Sulfhydryl content in PSN1-treated cancer cells incubated for 24 or 36 h with tested compounds 14–16. The sulfhydryl group amount was determined using the DTNB assay. Error bars indicate the S.D. **P < 0.01 compared with the control. (B) Effect of copper compounds on hydrogen peroxide formation in PSN-1 cells. PSN-1 cells were preincubated in PBS/10 mM glucose medium for 20 min at 37 °C in the presence of 10 μM CM-DCFDA and then treated with 10 μM of tested compounds.

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Interestingly, Cu(I) complexes 14 and 15 were completely ineffective in modulating the total thiol content in PSN1-treated cancer cells, whereas treatment with 16 induced a substantial time-dependent alteration of the total cellular sulfhydryl content, determining 18 and 25% reduction of thiol groups with respect to control untreated cells following 24 or 36 h of exposure, respectively (Figure 6A).
Consistently, treatment of PSN-1 cells with complex 16 determined a substantial time-dependent increase in cellular basal ROS production, whereas treatment with 14 and 15 did not result in an increase in the basal cellular ROS production (Figure 6B). Notably, treatment with 16 determined a substantial increase in basal hydrogen peroxide formation, which was even higher than that obtained with antimycin, a classical inhibitor of the mitochondrial respiratory chain at the level of complex III.
Overall, these results demonstrate that the newly developed Cu(II) complex 16 induced an oxidative shift in the redox status of PSN-1 cells. On the contrary, Cu(I) complexes 14 and 15 seemed to act through a mechanism of action that does not encompass oxidative stress induction.
A persistent increase in the rate of ROS production and the induction of thiol redox stress can in turn prompt the collapse of the mitochondrial membrane potential as well as the loss of the mitochondrial shape and integrity (swelling), possibly leading to the induction of cell apoptosis. (78) We hence evaluated the effect determined by treatment with complexes 14–16 in terms of the modification of mitochondrial pathophysiological characteristics, such as the mitochondrial membrane potential and induction of cell death.
For mitochondrial membrane potential detection, PSN-1 cells were treated with IC50 concentrations of the tested complexes, and the percentage of cells with the altered mitochondrial membrane potential was determined by means of the Mito-ID membrane potential kit. As evident by results depicted in Figure 7A, as expected, complex 16 induced a 31% decrease in the dye red fluorescence, rather similar to that induced by the reference compound carbonyl cyanide-m-chlorophenylhydrazone (CCCP), thus attesting a significant increase in the percentage of hypopolarized cells. On the other hand, 14 and 15 induced a slight (about 12 and 19%, respectively) increase in the dye red fluorescence, thus indicating a modest increase in cancer cell population with the hyperpolarized mitochondrial membrane potential.

Figure 7

Figure 7. (A) PSN-1 cells were treated for 24 h with IC50 concentrations of tested complexes or CCCP (3 μM). The mitochondrial membrane potential was determined using the Mito-ID membrane potential kit. Data are the means of three independent experiments. Error bars indicate the S.D. *P < 0.1 and **P < 0.01 compared with the control. (B) Hoechst staining of PSN-1 cells incubated for 48 h with IC50 doses of 14, 15, or 16.

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Considering these results, it is possible to state that Cu(I) complexes 14 and 15 possess a rather different mechanism of action compared to Cu(II) complex 16.
It has been widely described that Cu(I) and Cu(II) complexes can induce different types of cell death. In order to analyze the mechanism involved in the loss of cancer cell viability, we assessed the ability of selected complexes to induce cancer cell death by means of apoptosis. Figure 7B shows the results obtained upon monitoring the cellular morphological changes in PSN-1 cells treated for 48 h with IC50 doses of 14, 15, and 16 and stained with a Hoechst 33258 fluorescent probe. Compared with control cells, cells treated with 16 presented brightly stained nuclei and morphological features typical of cells undergoing apoptosis, such as chromatin condensation and fragmentation, thus confirming the ability of Cu(II) complex 16 to induce cancer cell death by means of apoptosis. Conversely, cells treated with 14 and 15 did not show any classical sign of apoptosis induction and appeared increased in size and ultrastructural complexity.
These data are consistent with those already obtained with other series of similarly unconjugated or differently conjugated (pyrazolyl)acetate complexes and once again point out to the importance of the development of Cu(I) species able to trigger paraptosis, a strategic approach toward cancer cells that have become resistant to the apoptosis inducer drugs. (49,52,73,74)
Altogether, these results clearly suggest that Cu(II) complex 16 triggers cancer cell death via an apoptotic pathway, whereas Cu(I) complexes 14 and 15 kill cancer cells by means of an apoptosis alternative cancer cell death, possibly paraptosis, that has been recognized as a strategic pathway in cancer cells that are resistant to apoptotic mechanisms. Paraptosis is a type of programmed cell death, morphologically distinct from apoptosis and necrosis. Defining features of paraptosis are cytoplasmic vacuolation and the lack of an apoptotic morphology (cell shrinkage, apoptotic bodies, chromatin condensation, and nuclear fragmentation). Like apoptosis and other types of programmed cell death, the cell is involved in causing its own death, and gene expression is required. (79)
Interestingly, the above discussed EXAFS data analysis revealed that in Cu(I) complex 15, the Cu–N nearest neighbor distance is slightly longer with respect to Cu(II) complexes 10 and 16, suggesting more loosely bound copper in complex 15, likely related to the lower electronegativity of Cu(I). This structural feature, potentially leading to a faster ligand exchange rate and reactivity, might be responsible for the higher antitumor efficacy of 15.
Considering all the collected data, complex 15 can be recommended for a more detailed investigation of its biological properties, such as the assessment of its interactions with important biomolecules and the evaluation of the in vivo efficacy.

Conclusions

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In this study, the known antitumor drug LND was functionalized with species able to coordinate metals, affording new heteroscorpionate ligands 1–4, which were used for the preparation of Cu(I) and Cu(II) complexes 5–16. In the solid state, a multitechnique approach (SR-XPS, NEXAFS, and XAFS) allowed us to ascertain the molecular stability of the ligands upon interaction with the copper ions, as well as to determine the coordination geometry and copper ion oxidation state.
From the biological studies, the following promising results emerged:
i

All the complexes showed an extremely promising cytotoxic activity in a panel of human tumor cell lines, eliciting IC50 values in the low or submicromolar range and being more effective than the reference metallodrug cisplatin.

ii

Noteworthily, they were able to overcome the oxaliplatin and multidrug resistance.

iii

They were also more effective than cisplatin against the more predictive 3D spheroids of pancreatic PSN-1 cancer cells. In particular, the lipophilic PPh3-containing Cu(I) complexes proved to be the most active compounds, with complex 15 being the most promising candidate.

iv

Representative complexes 14–16 were able to cross the cellular plasmalemma, and Cu accumulated differently in treated cancer cells with a direct correlation between cellular accumulation and cytotoxic potency, suggesting the involvement of different internalization mechanisms for Cu(I) and Cu(II) complexes.

v

More importantly, Cu(I) complexes proved to be ineffective in modulating cellular oxidative stress and induced cancer cell death via an apoptosis-alternative pathway, possibly paraptosis. On the contrary, Cu(II) complexes caused oxidative stress and triggered apoptotic cell death.

Based on their interesting biological profile, Cu(I) LND-conjugated complexes deserve to be further investigated, with the aim to find application in solid tumors, refractory to platinum-based drug treatment.

Experimental Section

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Chemistry

Materials and General Methods

All the reagents have been purchased and used without further purification. Melting points (mps) were performed using an SMP3 Stuart Scientific Instrument (Bibby Sterilin Ltd., London, UK). Elemental analyses (C, H, N, and S) (EA) were performed using a Fisons Instruments EA-1108 CHNS–O elemental analyzer (Thermo Fisher Scientific Inc., Waltham, MA, USA). Fourier transform infrared (FT-IR) spectra were recorded from 4000 to 700 cm–1 on a PerkinElmer Frontier instrument (PerkinElmer Inc., Waltham, MA, USA), equipped with an attenuated total reflection unit using a universal diamond top plate as a sample holder. Abbreviation used in the analyses of the FT-IR spectra: br = broad, m = medium, mbr = medium broad, s = strong, sbr = strong broad, sh = shoulder, vs = very strong, w = weak, and wbr = weak broad. NMR spectra for nuclei 1H, 13C, and 31P were recorded using a Bruker 500 Ascend spectrometer (Bruker BioSpin Corporation, Billerica, MA, USA; 500.1 MHz for 1H, 125 MHz for 13C, and 202.4 MHz for 31P). Tetramethylsilane [Si(CH3)4] was used as an external standard for the 1H and 13C NMR spectra, while 85% H3PO4 was used for the 31P NMR spectra. The chemical shifts (δ) are reported in parts per million. Abbreviation used in the analyses of the NMR spectra: br = broad, d = doublet, m = multiplet, s = singlet, sbr = singlet broad, t = triplet, and tbr = triplet broad. ESI-MS spectra were recorded in the positive- [ESI-MS(+)] or negative-ion [ESI-MS(−)] mode on a Waters Micromass ZQ spectrometer equipped with a single quadrupole (Waters Corporation, Milford, MA, USA), using a methanol or acetonitrile mobile phase. The compounds were added to reagent grade methanol or acetonitrile to give approximately 0.1 mM solutions. These solutions were injected (1 μL) into the spectrometer fitted with an autosampler. The pump delivered the solutions to the mass spectrometer source at a flow rate of 200 μL/min, and nitrogen was employed both as a drying gas and as a nebulizing gas. Capillary voltage was typically 2500 V. The temperature of the source was 100 °C, while the temperature of the desolvation was 400 °C. In the analyses of ESI-MS spectra, the confirmation of major peaks was supported by comparison of the observed and predicted isotope distribution patterns, the latter calculated using IsoPro 3.1 computer software (T-Tech Inc., Norcross, GA, USA).

Synthesis of 2-Hydroxyethyl-1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylate (LONES)

Sulfuric acid (2 mL) was added to a solution of LND (0.50 g, 1.56 mmol) in ethylene glycol (35 mL), and the reaction mixture was stirred at 85 °C for 1 h. After cooling to room temperature, the solution was poured into the ice water. The aqueous layer (50 mL) was extracted by dichloromethane (3 × 30 mL). The organic phase was dried over Na2SO4. The evaporation of the solvent under reduced pressure afforded a residue, which was purified using column chromatography, eluting with cyclohexane/EtOAc (6:4). A white solid was obtained (65% yield). mp: 121–122 °C. IR (cm–1): 3480mbr (O–H); 3084wbr, 2949wbr (C–H); 1713s (C═O); 1585m; 1560sh (C═C/C═N); 1479m, 1472s, 1446m, 1436s, 1421m, 1311s, 1275m, 1249s, 1225s, 1167s, 1157s, 1129s, 1096m, 1084s, 1044m, 1025m, 1009m, 990m, 977m, 944m, 898m, 855m, 839m, 807m, 789m, 776m, 747s, 737s. 1H NMR (CDCl3, 293 K): δ 4.07 (m, 2H, −CH2–OH), 4.65 (m, 2H, −CH2–O), 5.81 (s, 2H, N–CH2-Ph), 6.72 (d, 1H, ArH), 7.10–7.49 (m, 6H, ArH and OH), 8.28 (d, 1H, ArH). ESI-MS (major positive ions, CH3OH), m/z (%): 365 (20) [LONES + H]+, 387 (100) [LONES + Na]+, 753 (60) [2LONES + Na]+. ESI-MS (major negative ions, CH3OH), m/z (%): 363 (100) [LONES – H]−.

Synthesis of N-(2-Aminoethyl)-1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxamide (LONAM)

CDI (0.61 g, 3.74 mmol) was added to a solution of LND (1.00 g, 3.12 mmol) in anhydrous tetrahydrofuran (THF) (20 mL), and the mixture was stirred at room temperature for 1 h. After ethylenediamine (0.94 g, 15.6 mmol) was added, the solution was stirred at room temperature for 18 h. After evaporation of the solvent, the oil formed was dissolved in CHCl3 (30 mL) and washed with H2O (2 × 20 mL). The organic phase was dried over Na2SO4. The evaporation of the solvent under reduced pressure afforded a residue, which was purified using column chromatography, eluting with MeOH/EtOAc (1:9). A white solid was obtained (65% yield). mp: 71–72 °C. IR (cm–1): 3282br (N–H); 3060w, 3030w, 2937wbr (C–H); 1657sh, 1642s (C═O); 1620sh, 1588m; 1575m, 1538s (C═C/C═N); 1491s, 1473s, 1436s, 1406m, 1386m, 1372m, 1357m, 1310sbr, 1282m, 1233s, 1175s, 1155m, 1132m, 1097s, 1048s, 1005m, 968mbr, 942m, 859m, 836s, 788s, 772s, 742s. 1H NMR (CDCl3, 293 K): δ 3.01–3.58 (m, 4H, NH–CH2–CH2–NH), 4.87 (br, 2H, NH2), 5.64 (s, 2H, N–CH2–Ph), 6.63 (d, 1H, ArH), 7.02–7.48 (m, 6H, ArH and NH), 8.46 (d, 1H, ArH). ESI-MS (major positive ions, CH3OH), m/z (%): 363 (100) [LONAM + H]+, 385 (20) [LONAM + Na]+, 727 (40) [2LONAM + H]+. ESI-MS (major negative ions, CH3OH), m/z (%): 361 (100) [LONAM – H]−.

Synthesis of L1 (1)

A solution of HC(pz)2COOH (0.300 g, 1.560 mmol), LONES (0.624 g, 1.710 mmol), and DMAP (0.020 g, 0.157 mmol) in THF (20 mL) was cooled to 0 °C. EDCI·HCl (0.360 g, 1.880 mmol) was added, and the mixture was stirred for 16 h at room temperature. The reaction was then quenched with H2O (30 mL), and the aqueous phase was extracted with EtOAc (2 × 30 mL) The organic phase was washed with brine (2 × 20 mL) and dried over Na2SO4. The evaporation of the solvent afforded a residue, which was purified using column chromatography, eluting with cyclohexane/EtOAc (7:3). A white solid was obtained (72% yield). mp: 95–96 °C. IR (cm–1): 3121wbr, 2958wbr (C–H); 1762m, 1716mbr (C═O); 1616w; 1590w, 1564w, 1518w (C═C/C═N); 1476m, 1434m, 1387s, 1317m, 1291m, 1259m, 1221s, 1191m, 1156s, 1123s, 1088s, 1046s, 1008m, 967m, 948m, 916m, 884m, 835m, 817m, 801m, 788m, 748s. 1H NMR (DMSO-d6, 293 K): δ 4.52–4.61 (m, 4H, O–CH2–CH2–O), 5.89 (s, 2H, N–CH2–Ph), 6.26 (t, 2H, 4-CH), 6.96 (d, 1H, ArH), 7.37–8.01 (m, 11H, 3-CH, 5-CH, ArH and CHCO). 1H NMR (CDCl3, 293 K): δ 4.72 (m, 4H, O–CH2–CH2–O), 5.81 (s, 2H, N–CH2-Ph), 6.30 (m, 2H, 4-CH), 6.73 (d, 1H, ArH), 7.11–7.81 (m, 10H, 3-CH, 5-CH, ArH and CHCO), 8.15 (d, 1H, ArH). ESI-MS (major positive ions, CH3OH) m/z (%): 539 (20) [L1 + H]+, 561 (100) [L1 + Na]+. Calcd for C25H20Cl2N6O4: H, 3.74; C, 55.67; N, 15.58%. Found: H, 3.94; C, 55.33; N, 15.20%.

Synthesis of L2 (2)

This compound was prepared from HC(3,5-Me2pz)2COOH and LONES following the procedure described for L1 (1): a white solid was obtained (75% yield). mp: 139–140 °C. IR (cm–1): 3063wbr, 2958w, 2928w (C–H); 1763s, 1726sbr (C═O); 1616w; 1590m, 1562s (C═C/C═N); 1476s, 1416s, 1378s, 1316s, 1265s, 1218vs, 1202vs, 1156vs, 1123vs, 1102vs, 1048s, 1035vs, 1008s, 970s, 947m, 892m, 862m, 835s, 787vs, 748vs. 1H NMR (DMSO-d6, 293 K): δ 1.96 (s, 6H, CH3), 2.09 (s, 6H, CH3), 4.55–4.63 (m, 4H, O–CH2–CH2–O), 5.79 (s, 2H, N–CH2-Ph), 5.88 (s, 2H, 4-CH), 6.97 (d, 1H, ArH), 7.33–8.05 (m, 7H, ArH and CHCO). 1H NMR (CDCl3, 293 K): δ 2.11 (s, 6H, CH3), 2.14 (s, 6H, CH3), 4.74 (m, 4H, O–CH2–CH2–O), 5.81, (s, 2H, N–CH2-Ph), 5.83 (s, 2H, 4-CH), 6.73 (d, 1H, ArH), 7.06–8.16 (m, 7H, ArH and CHCO). ESI-MS (major positive ions, CH3OH), m/z (%): 595 (20) [L2 + H]+, 617 (100) [L2 + Na]+, 633 (20) [L2 + K]+, 1213 (10) [2L2 + Na]+. Calcd for C29H28Cl2N6O4: H, 4.74; C, 58.49; N, 14.11%. Found: H, 4.45; C, 58.71; N, 13.88%.

Synthesis of L3 (3)

A mixture of HC(pz)2COOH (0.156 g, 0.810 mmol), LONAM (0.330 g, 0.900 mmol), EDCI·HCl (0.230 g, 1.20 mmol), HOBt (0.160 g, 1.18 mmol), and triethylamine (0.107 mg, 1.06 mmol) in N,N-dimethylformamide (DMF) (10 mL) was stirred at room temperature for 16 h. The reaction was quenched with H2O (30 mL), and the aqueous phase was extracted with EtOAc (2 × 20 mL). The organic phase was washed with brine (3 × 20 mL) and NaHCO3 (3 × 20 mL) and dried over Na2SO4. The evaporation of the solvent afforded a residue, which was purified using column chromatography, eluting with cyclohexane/EtOAc (3:7). A white solid was obtained (68% yield). mp: 179–181 °C. IR (cm–1): 3275mbr, 3223m (N–H); 3075m, 2951m, (C–H); 1673vs, 1641vs (C═O); 1587m, 1539vs, 1515s (C═C/C═N); 1493s, 1473s, 1449s, 1433m, 1389vs, 1371s, 1313s, 1285s, 1249s, 1230vs, 1195s, 1177vs, 1154s, 1131m, 1112m, 1099s, 1092s, 1084s, 1064m, 1049vs, 1005m, 985w, 969m, 946m, 935m, 915m, 896w, 883w, 864s, 837vs, 812vs, 788s, 751vs. 1H NMR (DMSO-d6, 293 K): δ 3.30–3.47 (m, 4H, NH–CH2–CH2–NH), 5.83 (s, 2H, N–CH2-Ph), 6.27 (t, 2H, 4-CH), 6.78 (d, 1H, ArH), 7.25–8.64 (m, 13H, 3-CH, 5-CH, ArH, CHCO and NH). 1H NMR (CDCl3, 293 K): δ 3.69 (m, 4H, NH–CH2–CH2–NH), 5.67 (s, 2H, N–CH2-Ph), 6.26 (m, 2H, 4-CH), 6.68 (d 1H, ArH), 7.00–7.72 (m, 12H, 3-CH, 5-CH, ArH, CHCO and NH), 8.38 (d, 1H, ArH). ESI-MS (major positive ions, CH3OH), m/z (%): 559 (100) [L3 + Na]+, 1097 (30) [2L3 + Na]+. ESI-MS (major negative ions, CH3OH), m/z (%): 557 (100) [L3 – H]−. Calcd for C25H22Cl2N8O2: H, 4.13; C, 55.87; N 20.85%. Found: H, 3.97; C, 55.53; N, 20.59%.

Synthesis of L4 (4)

This compound was prepared from HC(3,5-Me2pz)2COOH and LONAM following the procedure described for L3 (3): a white solid was obtained (75% yield). mp: 170–172 °C. IR (cm–1): 3288br (N–H); 3070wbr, 2947wbr (C–H); 1669s, 1644s (C═O); 1590m, 1562sh, 1536s (C═C/C═N); 1491m, 1473s, 1456m, 1439s, 1415m, 1374s, 1363m, 1338m, 1312s, 1272s, 1246s, 1228s, 1198m, 1178s, 1154m, 1111m, 1099m, 1081m, 1050m, 1033m, 1028m, 1002m, 974m, 948m, 885m, 861m, 834s, 807s, 794m, 780s, 751vs, 740s, 709s. 1H NMR (DMSO-d6, 293 K): δ 2.02 (s, 6H, CH3), 2.08 (s, 6H, CH3), 3.37–3.47 (m, 4H, NH–CH2–CH2–NH), 5.81 (s, 2H, N–CH2-Ph), 5.83 (s, 2H, 4-CH), 6.74 (d, 1H, ArH), 6.91–8.38 (m, 9H, ArH, CHCO and NH). 1H NMR (CDCl3, 293 K): δ 2.09 (s, 6H, CH3), 2.30 (s, 6H, CH3), 3.62–3.76 (m, 4H, NH–CH2–CH2–NH), 5.66 (s, 2H, N–CH2-Ph), 5.80 (s, 2H, 4-CH), 6.67 (d, 1H, ArH), 6.97–8.36 (m, 8H, ArH, CHCO and NH). ESI-MS (major positive ions, CH3OH), m/z (%): 593 (100) [L4 + H]+, 615 (50) [L4 + Na]+. ESI-MS (major negative ions, CH3OH), m/z (%): 591 (100) [L4 – H]−. Calcd for C29H30Cl2N8O2: H, 5.10; C, 58.69; N, 18.88%. Found: H, 4.97; C, 58.43; N, 19.14%.

Synthesis of [(PTA)2Cu(L1)]PF6 (5)

PTA (0.117 g, 0.743 mmol) was added to a solution of Cu(CH3CN)4PF6 (0.139 g, 0.372 mmol) in acetonitrile (80 mL). The reaction mixture was stirred at room temperature for 4 h; then, L1 (1, 0.200 g, 0.372 mmol) was added, and the suspension was stirred overnight. The reaction mixture was filtered and dried under reduced pressure to give the crystalline white complex [(PTA)2Cu(L1)]PF6 (5) in 73% yield. mp: 147–150 °C. IR (cm–1): 3128wbr, 2937wbr (C–H); 1761m, 1718m (C═O); 1616w; 1590w, 1564w, 1519w (C═C/C═N); 1477m, 1446m, 1418m, 1403m, 1390m, 1289m, 1242m, 1218m, 1161m, 1126m, 1098m, 1049m, 1015m, 971s, 948m, 917w, 893w, 876w, 833vs, 817m, 789m, 752s, 742s. 1H NMR (DMSO-d6, 293 K): δ 4.07 (sbr, 12H, NCH2P), 4.41–4.65 (m, 16H, NCH2N and OCH2CH2O), 5.89 (s, 2H, NCH2Ph), 6.35 (sbr, 2H, 4-CH), 6.98 (d, 1H, ArH), 7.39–8.02 (m, 11H, 3-CH, 5-CH, CHCO and ArH). 13C NMR (DMSO-d6, 293 K): δ 49.7 (NCH2Ph); 50.2, 50.9 (CH2P); 64.2, 66.0 (OCH2CH2O); 71.4 (CH2N); 106.2 (4-CH); 110.4, 121.3, 123.1, 123.2, 127.0, 127.5, 128.8, 130.6, 130.7, 132.8, 140.6, 141.5 (ArH, Ar, CHCO, 3-CH and 5-CH); 160.8, 163.8 (CO). 31P{1H} NMR (DMSO-d6, 293 K): δ −144.18 (septet, J(F–P) = 711 Hz, PF6), −95.02 (br). 31P{1H} NMR (CD3CN, 293 K): δ −143.49 (septet, J(F–P) = 706 Hz, PF6), −90.42 (br). ESI-MS (major positive ions, CH3CN), m/z (%): 158 (20) [PTA + H]+, 603 (100) [Cu(L1)]+. ESI-MS (major negative ions, CH3CN), m/z (%): 145 (100) [PF6]−. Calcd for C37H44Cl2CuF6N12O4P3: H, 4.18; C, 41.84; N, 15.82%. Found: H, 4.12; C, 41.67; N, 15.47%.

Synthesis of [(PPh3)2Cu(L1)]PF6 (6)

This compound was prepared from PPh3 following the procedure described for 5. The obtained residue was filtered and dried under reduced pressure to give the crystalline white complex [(PPh3)2Cu(L1)]PF6 (6) in 74% yield. mp: 105–109 °C. IR (cm–1): 3133wbr, 3056wbr (C–H); 1765m, 1716mbr (C═O); 1616w; 1588m, 1564w, 1523w (C═C/C═N); 1479m, 1455m, 1435m, 1403m, 1353m, 1299m, 1286m, 1216m, 1161s, 1125m, 1095s, 1055m, 1027m, 1008m, 999m, 986m, 955m, 919w, 834vs, 788m, 742vs. 1H NMR (DMSO-d6, 293 K): δ 4.47 (sbr, 4H, OCH2CH2O), 5.88 (s, 2H, NCH2Ph), 6.28 (sbr, 2H, 4-CH), 6.98 (d, 1H, ArH), 7.26–7.99 (m, 41H, 3-CH, 5-CH, CHCO and ArH). 13C NMR (DMSO-d6, 293 K): δ 52.7 (NCH2Ph); 64.7, 67.2 (OCH2CH2O); 106.1 (4-CH); 110.6, 122.4, 122.6, 123.0, 128.6, 128.8, 129.1, 129.3, 129.4, 130.0, 131.7, 132.5, 132.6, 132.8, 133.0, 133.4, 133.8, 138.8, 142.4 (ArH, Ar, CHCO, 3-CH and 5-CH); 161.6, 163.9 (CO). 31P{1H} NMR (DMSO-d6, 293 K): δ −148.80 (septet, J(F–P) = 713 Hz, PF6), −3.33 (br). 31P{1H} NMR (CD3CN, 293 K): δ −143.51 (septet, J(F–P) = 705 Hz, PF6), 0.15 (br). ESI-MS (major positive ions, CH3CN), m/z (%): 587 (100) [Cu(PPh3)2]+, 603 (40) [Cu(L1)]+. ESI-MS (major negative ions, CH3CN), m/z (%): 145 (100) [PF6]−. Calcd for C61H50Cl2CuF6N6O4P3: H, 3.96; C, 57.58; N, 6.60%; Found: H, 3.98; C, 57.27; N, 6.39%.

Synthesis of [(L1)CuCl2] (7)

CuCl2·2H2O (0.063 g, 0.371 mmol) was added to an acetonitrile solution (80 mL) of L1 (1, 0.200 g, 0.371 mmol). The reaction mixture was stirred at room temperature for 24 h to obtain a precipitate, which was filtered, washed with acetonitrile, and dried under reduced pressure to give the green complex [(L1)CuCl2] (7) in 87% yield. mp: 193–195 °C. IR (cm–1): 3129w, 3112wbr, 2996w (C–H); 1748s, 1710s (C═O); 1591w, 1567w (C═C/C═N); 1500w, 1478m, 1452m, 1429m, 1403s, 1361w, 1301m, 1284m, 1254m, 1230m, 1220s, 1195m, 1168vs, 1129s, 1090s, 1060s, 1040m, 1008m, 994m, 953m, 920w, 891m, 852m, 818m, 800m, 781s, 764s, 751s. ESI-MS (major positive ions, CH3CN), m/z (%): 602 (100) [Cu(L1) – H]+. ESI-MS (major negative ions, CH3CN), m/z (%): 170 (100) [CuCl3]−. Calcd for C25H20Cl4CuN6O4: H, 2.99; C, 44.56; N, 12.47%. Found: H, 3.11; C, 44.80; N, 12.71%.

Synthesis of [(PTA)2Cu(L3)]PF6 (8)

This compound was prepared from L3 (3) following the procedure described for 5. The obtained residue was filtered and subsequently purified in diethyl ether (50 mL) and then in n-hexane (50 mL) to obtain the crystalline white complex [(PTA)2Cu(L3)]PF6 (8) in 57% yield. mp: 163–167 °C. IR (cm–1): 3281wbr (N–H); 3127wbr, 2936wbr (C–H); 1691mbr, 1652mbr (C═O); 1589w, 1537mbr (C═C/C═N); 1493m, 1474m, 1446m, 1417sh, 1403m, 1372mbr, 1291m, 1242m, 1177m, 1136w, 1099m, 1048m, 1015s, 970s, 949s, 917w, 894w, 833vs, 742sbr. 1H NMR (DMSO-d6, 293 K): δ 3.39 (s, 4H, NHCH2CH2NH), 4.07 (sbr, 12H, NCH2P), 4.40–4.64 (m, 12H, NCH2N), 5.83 (s, 2H, NCH2Ph), 6.42 (br, 2H, 4-CH), 6.78 (d, 1H, ArH), 7.32–8.01 (m, 10H, 3-CH, 5-CH, ArH and CHCO), 8.22 (d, 1H, ArH), 8.40 (tbr, 1H, NH), 8.46 (sbr, 1H, NH). 13C NMR (DMSO-d6, 293 K): δ 38.2 (NCH2CH2N); 50.0 (NCH2Ph); 50.3, 51.8 (CH2P); 72.3 (CH2N); 105.5; 107.1 (4-CH); 110.8 122.5, 122.7, 123.2, 127.7, 128.3, 129.5, 130.6, 132.4, 133.3, 133.7, 133.9, 138.5, 141.6 (ArH, Ar, CHCO, 3-CH and 5-CH); 162.5, 164.1 (CO). 31P{1H} NMR (DMSO-d6, 293 K): δ −144.19 (septet, J(F–P) = 711 Hz, PF6), −93.70 (sbr). 31P{1H} NMR (CD3CN, 293 K): δ −143.51 (septet, J(F–P) = 706 Hz, PF6), −91.0 (br). 31P{1H} NMR (CDCl3, 293 K): δ −143.80 (septet, J(F–P) = 714 Hz, PF6), −92.02 (sbr). ESI-MS (major positive ions, CH3CN), m/z (%): 158 (10) [PTA + H]+, 220 (5) [Cu(PTA)]+, 377 (30) [Cu(PTA)2]+, 601 (100) [Cu(L3)]+, 758 (10) [(PTA)Cu(L3)]+. ESI-MS (major negative ions, CH3CN), m/z (%): 145 (100) [PF6]−. Calcd for C37H46Cl2CuF6N14O2P3: H, 4.37; C, 41.92; N, 18.50%. Found: H, 4.58; C, 41.66; N, 18.18%.

Synthesis of [(PPh3)2Cu(L3)]PF6 (9)

This compound was prepared from PPh3 and L3 (3) following the procedure described for 5. The obtained residue was filtered and then purified in diethyl ether (50 mL) to obtain the white complex [(PPh3)2Cu(L3)]PF6 (9) in 65% yield. mp: 186–189 °C. IR (cm–1): 3399wbr, 3288wbr (N–H); 3128wbr, 3055wbr (C–H); 1702sh, 1674mbr (C═O); 1626m, 1615m; 1588m, 1540mbr (C═C/C═N); 1479m, 1435s, 1403m, 1373m, 1361m, 1289mbr, 1245mbr, 1231mbr, 1181mbr, 1119m, 1095m, 1056m, 1027m, 999m, 981mbr, 919wbr, 834vs, 741vs. 1H NMR (DMSO-d6, 293 K): δ 3.37–3.41 (m, 4H, NHCH2CH2NH), 5.82 (s, 2H, NCH2Ph), 6.36 (sbr, 2H, 4-CH), 6.79 (d, 1H, ArH), 7.31–7.97 (m, 40H, 3-CH, 5-CH, ArH and CHCO), 8.22 (d, 1H, ArH), 8.35 (tbr, 1H, NH), 8.65 (tbr, 1H, NH). 13C NMR (DMSO-d6, 293 K): δ 38.1 (NCH2CH2N); 50.0 (NCH2Ph); 107.1 (4-CH); 110.8, 122.5, 122.7, 123.2, 127.7, 128.3, 129.2, 129.4, 129.5, 130.8, 132.0, 132.5, 132.7, 132.9, 133.4, 133.8, 133.9, 138.5, 141.6, 141.9 (ArH, Ar, CHCO, 3-CH and 5-CH); 162.5, 164.0 (CO)·31P{1H} NMR (DMSO-d6, 293 K): δ −144.00 (septet, J(F–P) = 714 Hz, PF6), 0.35 (sbr). 31P{1H} NMR (CD3CN, 293 K): δ −143.53 (septet, J(F–P) = 707 Hz, PF6), 0.26 (sbr). ESI-MS (major positive ions, CH3CN), m/z (%): 587 (100) [Cu(PPh3)2]+, 601 (10) [Cu(L3)]+, 863 (20) [(PPh3)Cu(L3)]+. ESI-MS (major negative ions, CH3CN), m/z (%): 145 (100) [PF6]−. Calcd for C61H52Cl2CuF6N8O2P3: H, 4.13; C, 57.67; N, 8.82%. Found: H, 4.06; C, 57.38; N, 8.50%.

Synthesis of [(L3)CuCl2] (10)

This compound was prepared from L3 (3) following the procedure described for 7, using CH3OH as a solvent, to give the light blue complex [(L3)CuCl2] (10) in 68% yield. mp: 216–219 °C dec. IR (cm–1): 3494wbr, 3407m, 3290mbr (N–H); 3152w, 3121m, 3091m, 3065w, 2977w, 2943w, 2832w (C–H); 1672vs, 1659sh (C═O); 1565sbr, 1539s (C═C/C═N); 1491s, 1471s, 1450m, 1428m, 1406s, 1384s, 1361m, 1330s, 1313s, 1282vs, 1244s, 1230s, 1205m, 1197m, 1172s, 1150m, 1130m, 1095s, 1063vs, 1046m, 1026m, 1007s, 990s, 956m, 942m, 924m, 892m, 861s, 841s, 833vs, 787vs, 765vs, 748vs, 729s. ESI-MS (major positive ions, CH3CN), m/z (%): 537 (80) [L3 + H]+, 559 (100) [L3 + Na]+, 600 (55) [Cu(L3) – H]+, 1097 (40) [2L3 + Na]+, 1137 (20) [Cu(L3)2]+. ESI-MS (major negative ions, CH3CN), m/z (%): 170 (10) [CuCl3]−, 573 (100) [L3 + Cl]−. Calcd for C25H22Cl4CuN8O2: H, 3.30; C, 44.69; N, 16.68%. Found: H, 3.52; C, 45.02; N, 16.34%.

Synthesis of [(PTA)2Cu(L2)]PF6 (11)

This compound was prepared from L2 (2) following the procedure described for 5. The reaction was filtered, and the solution was dried under reduced pressure to give the white complex [(PTA)2Cu(L2)]PF6 (11) in 94% yield. mp: 187–191 °C. IR (cm–1): 3080br, 2985sh, 2950sh, 2925wbr, 2893sh (C–H); 1763m, 1719mbr (C═O); 1647wbr, 1616wbr; 1590w, 1563m (C═C/C═N); 1475m, 1449m, 1418m, 1389m, 1316m, 1297mbr, 1268mbr, 1242m, 1218mbr, 1163mbr, 1123m, 1104m, 1043mbr, 1014s, 969sbr, 948s, 895m, 874sh, 834vs, 803sh, 744s, 718m. 1H NMR (DMSO-d6, 293 K): δ 2.05 (s, 6H, CH3), 2.36 (s, 6H, CH3), 4.04 (s, 12H, NCH2P), 4.40–4.73 (m, 16H, NCH2N and OCH2CH2O), 5.79–5.96 (m, 4H, NCH2Ph and 4-CH), 6.90–8.03 (m, 8H, CHCO and ArH). 13C NMR (DMSO-d6, 293 K): δ 11.0 (CH3); 14.3 (CH3); 50.3 (NCH2Ph); 50.5, 51.8 (CH2P); 72.4 (CH2N); 65.1, 66.7 (OCH2CH2O); 106.2 (4-CH); 111.3, 122.0, 123.2, 123.9, 127.9, 128.2, 129.6, 131.6, 133.5, 135.0, 141.4, 144.3, 148.2, 151.4 (ArH, Ar, CHCO, 3-CH and 5-CH); 161.9, 163.4 (CO). 31P{1H} NMR (DMSO-d6, 293 K): δ −144.19 (septet, J(F–P) = 711 Hz, PF6), −92.78 (sbr). 31P{1H} NMR (CD3CN, 293 K): δ −143.52 (septet, J(F–P) = 706 Hz, PF6), −94.0 (br). ESI-MS (major positive ions, CH3CN), m/z (%): 659 (100) [Cu(L2)]+. ESI-MS (major negative ions, CH3CN), m/z (%): 145 (100) [PF6]−. Calcd for C41H52Cl2CuF6N12O4P3: H, 4.69; C, 44.03; N, 15.03%. Found: H, 4.80; C, 43.77; N, 14.78%.

Synthesis of [(PPh3)2Cu(L2)]PF6 (12)

This compound was prepared from PPh3 and L2 (2) following the procedure described for 5. The reaction was filtered, and the solution was dried under reduced pressure. Then, the residue in the round-bottom flask was purified with hot diethyl ether (3 × 30 mL) to give the white complex [(PPh3)2Cu(L2)]PF6 (12) in 51% yield. mp: 118–122 °C. IR (cm–1): 3055wbr, 2959wbr, 2924wbr (C–H); 1763m, 1718mbr (C═O); 1635w, 1616w; 1588w, 1563m (C═C/C═N); 1478m, 1435m, 1422sh, 1389m, 1315m, 1265mbr, 1217mbr, 1163m, 1123m, 1095m, 1049m, 1029m, 1008w, 998m, 961w, 896w, 875m, 837vs, 789m, 743s. 1H NMR (DMSO-d6, 293 K): δ 1.92 (s, 6H, CH3), 2.41 (s, 6H, CH3), 3.70, 4.27 (sbr, 4H, OCH2CH2O), 5.88 (s, 2H, NCH2Ph), 6.02 (s, 2H, 4-CH), 7.07 (d, 1H, ArH), 7.28–7.71 (m, 35H, CHCO and ArH), 7.93 (d, 1H, ArH), 8.05 (d, 1H, ArH). 13C NMR (DMSO-d6, 293 K): δ 11.1 (CH3); 14.4 (CH3); 50.7 (NCH2Ph); 64.8, 66.3 (OCH2CH2O); 107.2 (4-CH); 111.3, 122.0, 123.3, 123.9, 128.0, 128.4, 130.0, 131.6, 133.6, 135.2, 141.7, 141.8, 144.2, 151.3 (ArH, Ar, CHCO, 3-CH and 5-CH); 161.8, 164.4 (CO). 31P{1H} NMR (DMSO-d6, 293 K): δ −144.20 (septet, J(F–P) = 710 Hz, PF6), −1.97 (sbr). ESI-MS (major positive ions, CH3CN), m/z (%): 587 (100) [Cu(PPh3)2]+, 659 (80) [Cu(L2)]+, 921 (10) [(PPh3)Cu(L2)]+. ESI-MS (major negative ions, CH3CN), m/z (%): 145 (100) [PF6]−. Calcd for C65H58Cl2CuF6N6O4P3: H, 4.40; C, 58.76; N, 6.33%. Found: H, 4.23; C, 58.42; N, 6.06%.

Synthesis of [(L2)CuCl2] (13)

CuCl2·2H2O (0.061 g, 0.359 mmol) was added to an acetonitrile solution (80 mL) of L2 (2, 0.214 g, 0.359 mmol). The reaction was stirred at room temperature for 24 h and dried under reduced pressure. Subsequently, the raw product was recrystallized using CH3CN/Et2O in a 1:10 ratio to obtain the dark green complex [(L2)CuCl2] (13) in 60% yield. mp: 148–150 °C. IR (cm–1): 3137mbr, 2960mbr, 2926mbr, 2856mbr (C–H); 1765m, 1716mbr (C═O); 1590m, 1563m (C═C/C═N); 1472m, 1442m, 1419m, 1386m, 1316m, 1273m, 1217s, 1162s, 1124s, 1105s, 1047s, 1007m, 954mbr, 899m, 858m, 835m, 788s, 752s, 721m, 708m. ESI-MS (major positive ions, CH3CN), m/z (%): 658 (100) [Cu(L2) – H]+. ESI-MS (major negative ions, CH3CN), m/z (%): 170 (100) [CuCl3]−. Calcd for C29H28Cl4CuN6O4: H, 3.87; C, 47.72; N, 11.51%. Found: H, 3.94; C, 47.48; N, 11.23%.

Synthesis of [(PTA)2Cu(L4)]PF6 (14)

This compound was prepared from L4 (4) following the procedure described for 5. The reaction mixture was filtered, and the solution was dried under reduced pressure to obtain the white complex [(PTA)2Cu(L4)]PF6 (14) in 47% yield. mp: 227–230 °C. IR (cm–1): 3389wbr, 3252wbr (N–H); 2923wbr, 2887wbr (C–H); 1692m, 1658mbr (C═O); 1590w, 1562m, 1533mbr (C═C/C═N); 1493m, 1472m, 1449m, 1416m, 1388m, 1373m, 1314m, 1295mbr, 1267m, 1242m, 1230sh, 1176m, 1158sh, 1135w, 1104m, 1042mbr, 1013s, 968sbr, 948s, 894m, 874m, 833vs, 806sh, 776sh, 744s, 729s. 1H NMR (DMSO-d6, 293 K): δ 2.19 (s, 6H, CH3), 2.37 (s, 6H, CH3), 3.36–3.48 (m, 4H, NHCH2CH2NH), 4.04–4.66 (m, 24H, NCH2P and NCH2N), 5.82 (s, 2H, NCH2Ph), 6.10 (sbr, 2H, 4-CH), 6.76 (d, 1H, ArH), 6.92 (s, 1H, CHCO), 7.33–7.79 (m, 5H, ArH), 8.22 (d, 1H, ArH), 8.43 (br, 1H, NH), 9.07 (br, 1H, NH). 13C NMR (DMSO-d6, 293 K): δ 11.1 (CH3); 14.4 (CH3); 38.3 (NCH2CH2N); 50.0 (NCH2Ph); 50.5, 51.9 (CH2P); 72.4 (CH2N); 107.0 (4-CH); 110.8, 122.5, 122.7, 123.2, 127.7, 128.3, 129.6, 130.6, 133.3, 133.7, 133.9, 138.5, 141.6, 142.3 (ArH, Ar, CHCO, 3-CH and 5-CH); 162.6, 164.2 (CO). 31P{1H}-NMR (DMSO-d6, 293 K): δ −144.02 (septet, J(F–P) = 714 Hz, PF6), −92.29 (s). ESI-MS (major positive ions, CH3CN), m/z (%): 657 (100) [Cu(L4)]+, 814 (25) [(PTA)Cu(L4)]+. ESI-MS (major negative ions, CH3CN), m/z (%): 145 (100) [PF6]−. Calcd for C41H54Cl2CuF6N14O2P3: H, 4.88; C, 44.11; N, 17.57%. Found: H, 4.61; C, 43.80; N, 17.21%.

Synthesis of [(PPh3)2Cu(L4)]PF6 (15)

This compound was prepared from PPh3 and L4 (4) following the procedure described for 5. The reaction mixture was filtered, and the solution was dried under reduced pressure. Then, the residue in the round-bottom flask was solubilized with CHCl3 (10 mL) and filtered, and the solution was dried under reduced pressure to give the white complex [(PPh3)2Cu(L4)]PF6 (15) in 54% yield. mp: 100–105 °C. IR (cm–1): 3401wbr, 3284wbr (N–H); 3056wbr, 2926wbr, 2869wbr (C–H); 1694sh, 1672mbr (C═O); 1587m, 1562m, 1535m (C═C/C═N); 1492m, 1476m, 1435s, 1388m, 1311m, 1271m, 1230m, 1177m, 1158m, 1096m, 1071m, 1048m, 1028m, 998m, 918w, 835vs, 742vs. 1H NMR (DMSO-d6, 293 K): δ 1.82 (sbr, 6H, CH3), 2.43 (s, 6H, CH3), 3.37–3.41 (m, 4H, NHCH2CH2NH), 5.80 (s, 2H, NCH2Ph), 6.08 (s, 2H, 4-CH), 6.79 (d, 1H, ArH), 7.07 (s, 1H, CHCO), 7.26–7.52 (m, 33H, ArH), 7.73 (d, 1H, ArH), 7.79 (d, 1H, ArH), 8.20 (d, 1H, ArH), 8.38 (t, 1H, NH), 9.35 (tbr, 1H, NH). 13C NMR (DMSO-d6, 293 K): δ 11.0 (CH3); 13.8 (CH3); 37.6 (NCH2CH2N); 50.0 (NCH2Ph); 107.2 (4-CH); 110.8, 122.5, 122.8, 123.2, 127.7, 128.2, 129.4, 129.6, 129.8, 130.8, 131.9, 132.0, 132.5, 133.4, 133.7, 133.8, 138.5, 141.6, 143.0, 150.5 (ArH, Ar, CHCO, 3-CH and 5-CH); 162.6, 164.5 (CO). 31P{1H} NMR (DMSO-d6, 293 K): δ −144.20 (septet, J(F–P) = 711 Hz, PF6), 4.99 (s). 31P{1H} NMR (CD3CN, 293 K): δ −143.53 (septet, J(F–P) = 705 Hz, PF6), −1.06 (sbr). ESI-MS (major positive ions, CH3CN), m/z (%): 587 (100) [Cu(PPh3)2]+, 657 (15) [Cu(L4)]+, 919 (45) [(PPh3)Cu(L4)]+. ESI-MS (major negative ions, CH3CN), m/z (%): 145 (100) [PF6]−. Calcd for C65H60Cl2CuF6N8O2P3: H, 4.56; C, 58.85; N, 8.45%. Found: H, 4.27; C, 58.51; N, 8.12%.

Synthesis of [(L4)CuCl2] (16)

This compound was prepared from L4 (4) following the procedure described for 7, using CH3OH as a solvent, to give the light blue complex [(L4)CuCl2] (16) in 83% yield. mp: 248–250 °C. IR (cm–1): 3426wbr (N–H); 3169wbr, 2904mbr, 2799mbr (C–H); 1669s, 1620sh (C═O); 1576m, 1559s (C═C/C═N); 1528s, 1493m, 1467m, 1448m, 1428m, 1415m, 1397m, 1384m, 1375m, 1349m, 1314m, 1268w, 1248m, 1220m, 1194m, 1177m, 1157m, 1133m, 1116m, 1103m, 1064m, 1042m, 1005m, 987m, 949w, 913m, 875m, 861m, 837s, 807m, 787s, 754s, 744s, 708m. ESI-MS (major positive ions, CH3CN), m/z (%): 1248 (100) [Cu(L4)2 – H]+. ESI-MS (major negative ions, CH3CN), m/z (%): 170 (100) [CuCl3]−. Calcd for C29H30Cl4CuN8O2: H, 4.15; C, 47.85; N, 15.39%. Found: H, 4.43; C, 48.02; N, 15.09%.

Spectroscopic Methods

Synchrotron Radiation-Induced X-ray Photoelectron Spectroscopy

SR-XPS measurements were performed at the Materials Science Beamline (MSB) at the ELETTRA synchrotron radiation source (Trieste, Italy). The MSB is placed at the left end of the bending magnet 6.1, and it is equipped with a plane grating monochromator that provides light in the energy range of 21–1000 eV. The base pressure in the UHV end-station is of 2 × 10–10 mbar; the end-station is equipped with a SPECS PHOIBOS 150 hemispherical electron analyzer, low-energy electron diffraction optics, a dual-anode Mg/Al X-ray source, an ion gun, and a sample manipulator with a K-type thermocouple attached to the rear side of the sample. For this experiment, we detected photoelectrons emitted by C 1s, N 1s, Cl 2p, Cu 2p, and O 1s core levels at the normal emission geometry. A photon energy of 650 eV impinging at 60° was selected for all signals, with the aim to maximize especially the N 1s signal intensity; Cu 2p spectra were also collected using the Al Kα anode source (1487.0 eV) so as to maximize its photoemission signal. Charging correction of BEs was always performed using the aromatic C 1s signal as a reference (BE 284.70 eV). (80) To fit core-level spectra, we subtracted a Shirley background and then used Gaussian peak functions as signal components. (81,82) The BE resolution was 0.6 eV for all measured core levels.

NEXAFS Spectroscopy

NEXAFS spectroscopy experiments were performed at the ELETTRA storage ring at the BEAR (Bending Magnet for Emission Absorption and Reflectivity) beamline, installed at the left exit of the 8.1 bending magnet exit. The apparatus is based on a bending magnet as a source, a beamline optics delivering photons from 5 eV up to about 1600 eV with a selectable degree of ellipticity. The carbon and nitrogen K-edge spectra were collected at grazing (20°), magic (54.7°), and normal (90°) incidence angles of the linearly polarized photon beam with respect to the sample surface. The photon energy and resolution were calibrated and experimentally tested at the K absorption edges of Ar, N2, and Ne. The normalization procedure consists of three steps: (i) the energy calibration, in which the I0 reference current (drain current) of the sample is shifted on the I0 reference current (drain current) of the Au clean sample recorded; (ii) the signal is obtained from the double ratio after the interpolation of each signal to the Au reference. The double ratio allows us to correct for variations of the incident X-ray intensity with time as a function of photon energy due to instabilities of the electron beam in the storage ring or to changes of the X-ray optics in the beamline; (62) and (iii) finally, the signal is reduced to the standard form through a pre-edge and post-edge fit: a linear pre-edge background is subtracted from the data and a linear post-edge fit is applied to the post-edge region to evaluate the jump and obtain the normalized signal.

X-ray Absorption Fine Structure

XAFS Cu K-edge (ECu = 8980 eV) experiments were performed at the XAFS beamline (83) of the ELETTRA (Trieste) storage ring (complexes 10 and 16) and the B18 beamline (84) of the Diamond Light Source (UK) (complex 15). Complexes 10 and 16 were measured in the transmission geometry at LN temperature. Samples were prepared in the form of solid homogeneous pellets, in which the weight ratio between the PVP matrix and the Cu complex sample was approximately 5:1. Complex 15 was measured in the fluorescence geometry using a 36 element Ge detector. The sample was homogeneously mixed with boron nitride, pressed into a pellet, and measured at 77 K using a liquid nitrogen cryostat. The data were treated using the standard procedure for data normalization and extraction of the structural EXAFS signal χexp(k). (85) The quantitative EXAFS data analysis was carried out using program FitEXA. (85) The least squares method was used to minimize the difference between the experimental k2-weighted EXAFS function k2χexp(k) and the theoretical one k2χteo(k) in the reciprocal space 3 to 15 k–1. The model function was built as a sum of Gaussian-shaped shells, representative of the neighbor atoms around the absorber
Each shell is defined by three parameters: the number of neighbors N (multiplicity), the average distance Ri, and the MSRD parameter σi2, representing the variance of the scattering (SS or MS) path distribution. The So2 parameter, taking into account many body losses, was fixed to be 0.9. The same energy shift was used for all the contributions. The amplitude Ai, phase shift φi, and mean free path λ functions were calculated using FEFF 8.2 program (86) using the molecular geometry around the absorber.

Experiments with Cultured Human Cancer Cells

Cu(I) and Cu(II) complexes and the corresponding uncoordinated ligands and precursors were dissolved in DMSO just before the experiment, and a calculated amount of drug solution was added to the cell growth medium to a final solvent concentration of 0.5%, which had no detectable effects on cell viability. Cisplatin (Sigma Chemical Co, St. Louis, USA) and oxaliplatin (Sigma Chemical Co.) were dissolved in 0.9% sodium chloride solution.

Cell Cultures

Human lung (H157), colon (HCT-15 and LoVo), and pancreatic (PSN-1) carcinoma cells were obtained from the American Type Culture Collection (ATCC, Rockville, MD, USA). Human cervical carcinoma A431 cells were kindly provided by Prof. F. Zunino (Division of Experimental Oncology B, Istituto Nazionale dei Tumori, Milan). Human ovarian adenocarcinoma 2008 cells were kindly provided by Prof. G. Marverti (Dipartimento di Scienze Biomediche, Università di Modena University, Italy). Human colon cancer cells resistant to doxorubicin (LoVo MDR) were kindly provided by Prof. M. P. Rigobello (Dipartimento di Scienze Biomediche, Università di Padova, Italy). The LoVo-OXP cells were derived, using a standard protocol, by growing LoVo cells in increasing concentrations of OXP and following 17 months of selection of resistant clones, as previously described. (23)
Cell lines were maintained in the logarithmic phase at 37 °C in a 5% carbon dioxide atmosphere using the following culture media containing 10% fetal calf serum (EuroClone, Milan, Italy), antibiotics (50 units/mL penicillin and 50 μg/mL streptomycin), and 2 mM l-glutamine: (i) RPMI-1640 medium (EuroClone) for A431, PSN-1, H157, HCT-15, and 2008 cells and (ii) Ham’S F-12 (Sigma Chemical Co.) for LoVo, LoVo MDR, and LoVo-OXP cells.

MTT Assay

The growth inhibitory effect toward tumor cells was evaluated by means of an MTT assay. (23) Briefly, 3–8 × 103 cells/well, dependent upon the growth characteristics of the cell line, were seeded in 96-well microplates in growth medium (100 μL). After 24 h, the medium was removed and replaced with a fresh one containing the compound to be studied at the appropriate concentration. Triplicate cultures were established for each treatment. After 72 h, each well was treated with 10 μL of a 5 mg/mL MTT saline solution, and following 5 h of incubation, 100 μL of a sodium dodecyl sulfate solution in HCl 0.01 M was added. After overnight incubation, cell growth inhibition was detected by measuring the absorbance of each well at 570 nm using a Bio-Rad 680 microplate reader. Mean absorbance for each drug dose was expressed as a percentage of the control untreated well absorbance and plotted versus drug concentration. IC50 values, the drug concentrations that reduce the mean absorbance at 570 nm to 50% of those in the untreated control wells, were calculated using the four-parameter logistic (4-PL) model. Evaluation was based on the mean from at least four independent experiments.

Spheroid Cultures

Spheroid cultures were obtained by seeding 2.5 × 103 PSN-1 cancer cells/well in a round-bottom nontreated tissue culture 96-well plate (Greiner Bio-one, Kremsmünster, Austria) in phenol red free RPMI-1640 medium (Sigma Chemical Co.) containing 10% fetal calf serum and supplemented with 20% methyl cellulose stock solution.

APH Assay

An APH modified assay was used for determining cell viability in 3D spheroids, as previously described. (87) IC50 values were calculated using a 4-PL model.

Copper Cellular Accumulation

PSN-1 cells (2.5 × 106) were seeded in 75 cm2 flasks in growth medium (20 mL). After 24 h, the medium was replaced, and the cells were incubated for 24 h with tested complexes. Monolayers were then washed twice with ice-cold phosphate-buffered saline (PBS), harvested, and counted. Cell samples were subjected to five freeze–thaw cycles at −80 °C and then vigorously vortexed. The samples were treated with highly pure nitric acid and transferred into a microwave Teflon vessel. Samples were then submitted to standard mineralization procedures and analyzed for the copper amount by using a Varian AA Duo graphite furnace atomic absorption spectrometer (Varian, Palo Alto, CA; USA) at 324 nm. The calibration curve was obtained using known concentrations of standard solutions purchased from Sigma Chemical Co.

ROS Production

The production of ROS was measured in PSN-1 cells (104 per well) grown for 24 h in a 96-well plate in RPMI medium without phenol red (Sigma Chemical Co.). Cells were then washed with PBS and loaded with 10 μM 5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate acetyl ester (CM-H2DCFDA) (Molecular Probes-Invitrogen, Eugene, OR) for 25 min in the dark. Afterward, cells were washed with PBS and incubated with increasing concentrations of tested compounds. Fluorescence increase was estimated utilizing a plate reader (Tecan Infinite M200 PRO, Männedorf, Switzerland) at 485 nm (excitation) and 527 nm (emission). Antimycin (3 μM, Sigma Chemical Co), a potent inhibitor of Complex III in the electron transport chain, and auranofin were used as positive controls.

Quantification of Thiols

The PSN-1 cells (2 × 105) were seeded in a six-well plate in growth medium (4 mL). After 24 h, cells were incubated for 24 h with increasing concentrations of tested compounds. Subsequently, the thiol content was measured as previously described. (88)

Mitochondrial Membrane Potential

The mitochondrial membrane potential (ΔΨ) was assayed using the Mito-ID membrane potential kit according to the manufacturer’s instructions (Enzo Life Sciences, Farmingdale, NY). Briefly, PSN-1 cells (8 × 103 per well) were seeded in 96-well plates; after 24 h, cells were washed with PBS and loaded with the Mito-ID detection reagent for 30 min at 37 °C in the dark. Afterward, cells were incubated with increasing concentrations of tested complexes. Fluorescence intensity was estimated using a plate reader (Tecan Infinite M200 PRO, Männedorf, Switzerland) at 490 (excitation) and 590 nm (emission). CCCP (4 μM, Sigma Chemical Co), a chemical inhibitor of the oxidative phosphorylation, was used as the positive control.

Apoptosis Induction

PSN-1 cells were seeded into 8-well tissue culture slides (BD Falcon, Bedford, MA, USA) at 5 × 104 cells/well (0.8 cm2). After 24 h, the cells were washed twice with PBS, and following 48 h of treatment with IC50 doses of tested compounds, cells were stained for 5 min with 10 μg/mL Hoechst 33258 [20-(4-hydroxyphenyl)-5-(4-methyl-1-piperazinyl)-2,50-bi-1H-benzimidazole trihydrochloride hydrate, Sigma-Aldrich, St. Louis, MI, USA] in PBS. Samples were examined at 5× and 40× magnification in a Zeiss LSM 800 confocal microscope using the Zeiss ZEN 2.3 software system.

Statistical Analysis

All values are the means ± S.D. of no less than three measurements starting from three different cell cultures. Multiple comparisons were made using ANOVA, followed by the Tukey–Kramer multiple comparison test (*P < 0.05, **P < 0.01), using GraphPad software.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.inorgchem.1c03658.

  • EXAFS data analysis details; XPS data analysis results: BE, FWHM, atomic percents, and proposed assignments; XPS Cu 2p spectra of Cu(II) complex 10 (A) and Cu(I) complex 15 (B); and stability studies, where all complexes were dissolved at 50 μM in 0.5% DMSO/RPMI medium and UV–visible spectra were recorded at t = 0 min and t = 1440 min = 24 h (PDF)

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Author Information

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  • Corresponding Authors
  • Authors
    • Fabio Del Bello - School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032 Camerino, Italy;  Orcidhttps://orcid.org/0000-0001-6538-6029
    • Luca Bagnarelli - School of Science and Technology, Chemistry Division, University of Camerino, via S. Agostino 1, 62032 Camerino, Italy
    • Carlo Santini - School of Science and Technology, Chemistry Division, University of Camerino, via S. Agostino 1, 62032 Camerino, Italy;  Orcidhttps://orcid.org/0000-0002-3942-1713
    • Gianfabio Giorgioni - School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032 Camerino, Italy;  Orcidhttps://orcid.org/0000-0002-9576-6580
    • Alessandro Piergentili - School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032 Camerino, Italy;  Orcidhttps://orcid.org/0000-0001-6135-6826
    • Chiara Battocchio - Department of Science, Roma Tre University, Via della Vasca Navale 79, 00146 Roma, Italy;  Orcidhttps://orcid.org/0000-0003-4590-0865
    • Giovanna Iucci - Department of Science, Roma Tre University, Via della Vasca Navale 79, 00146 Roma, Italy;  Orcidhttps://orcid.org/0000-0002-6478-3759
    • Irene Schiesaro - Department of Science, Roma Tre University, Via della Vasca Navale 79, 00146 Roma, Italy
    • Carlo Meneghini - Department of Science, Roma Tre University, Via della Vasca Navale 79, 00146 Roma, Italy;  Orcidhttps://orcid.org/0000-0003-4846-8422
    • Iole Venditti - Department of Science, Roma Tre University, Via della Vasca Navale 79, 00146 Roma, Italy;  Orcidhttps://orcid.org/0000-0002-9306-573X
    • Nitya Ramanan - Diamond Light Source, Harwell Science and Innovation Campus, Didcot OX11 0DE, U.K.
    • Michele De Franco - Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131 Padova, Italy
    • Paolo Sgarbossa - Department of Industrial Engineering, University of Padova, via Marzolo 9, 35131 Padova, Italy;  Orcidhttps://orcid.org/0000-0002-0938-953X
    • Cristina Marzano - Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131 Padova, Italy
    • Valentina Gandin - Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131 Padova, Italy
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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This work was supported by grants from the University of Camerino (Fondo di Ateneo per la Ricerca 2019). We are grateful to the CIRCMSB (Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici). The Grant of Excellence Departments MIUR (ARTICOLO 1, COMMI 314–337 LEGGE 232/2016) is gratefully acknowledged by authors of Roma Tre University. This research was partially funded by Regione Lazio, through Progetto di ricerca 85-2017-15125, according to L.R.13/08. The authors of Roma Tre University acknowledge the CERIC-ERIC Consortium for the access to experimental facilities and financial support.

References

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    Cervantes-Madrid Diana; Romero Yair; Duenas-Gonzalez Alfonso
    BioMed research international (2015), 2015 (), 690492 ISSN:.
    Abnormal metabolism is another cancer hallmark. The two most characterized altered metabolic pathways are high rates of glycolysis and glutaminolysis, which are natural targets for cancer therapy. Currently, a number of newer compounds to block glycolysis and glutaminolysis are being developed; nevertheless, lonidamine and 6-diazo-5-oxo-L-norleucine (DON) are two old drugs well characterized as inhibitors of glycolysis and glutaminolysis, respectively, whose clinical development was abandoned years ago when the importance of cancer metabolism was not fully appreciated and clinical trial methodology was less developed. In this review, a PubMed search using the words lonidamine and 6-diazo-5-oxo-L-norleucine (DON) was undertaken to analyse existing information on the preclinical and clinical studies of these drugs for cancer treatment. Data show that they exhibit antitumor effects; besides there is also the suggestion that they are synergistic. We conclude that lonidamine and DON are safe and potentially effective drugs that need to be reevaluated in combination as metabolic therapy of cancer.
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  3. 3
    Guo, L.; Shestov, A. A.; Worth, A. J.; Nath, K.; Nelson, D. S.; Leeper, D. B.; Glickson, J. D.; Blair, I. A. Inhibition of Mitochondrial Complex II by the Anticancer Agent Lonidamine. J. Biol. Chem. 2016, 291, 42– 57,  DOI: 10.1074/jbc.M115.697516
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    3
    Inhibition of Mitochondrial Complex II by the Anticancer Agent Lonidamine
    Guo, Lili; Shestov, Alexander A.; Worth, Andrew J.; Nath, Kavindra; Nelson, David S.; Leeper, Dennis B.; Glickson, Jerry D.; Blair, Ian A.
    Journal of Biological Chemistry (2016), 291 (1), 42-57CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
    The antitumor agent lonidamine (LND; 1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid) is known to interfere with energy-yielding processes in cancer cells. However, the effect of LND on central energy metab. has never been fully characterized. In this study, we report that a significant amt. of succinate is accumulated in LND-treated cells. LND inhibits the formation of fumarate and malate and suppresses succinate-induced respiration of isolated mitochondria. Utilizing biochem. assays, we detd. that LND inhibits the succinate-ubiquinone reductase activity of respiratory complex II without fully blocking succinate dehydrogenase activity. LND also induces cellular reactive oxygen species through complex II, which reduced the viability of the DB-1 melanoma cell line. The ability of LND to promote cell death was potentiated by its suppression of the pentose phosphate pathway, which resulted in inhibition of NADPH and glutathione generation. Using stable isotope tracers in combination with isotopologue anal., we showed that LND increased glutaminolysis but decreased reductive carboxylation of glutamine-derived α-ketoglutarate. Our findings on the previously uncharacterized effects of LND may provide potential combinational therapeutic approaches for targeting cancer metab.
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  4. 4
    Sadeghi, R. N.; Karami-Tehrani, F.; Salami, S. Targeting prostate cancer cell metabolism: impact of hexokinase and CPT-1 enzymes. Tumor Biol. 2015, 36, 2893– 2905,  DOI: 10.1007/s13277-014-2919-4
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    4
    Targeting prostate cancer cell metabolism: impact of hexokinase and CPT-1 enzymes
    Sadeghi, Rouhallah Najjar; Karami-Tehrani, Fatemeh; Salami, Siamak
    Tumor Biology (2015), 36 (4), 2893-2905CODEN: TUMBEA; ISSN:1010-4283. (Springer)
    Glycolysis has been shown to be required for the cell growth and proliferation in several cancer cells. However, prostate cancer cells were accused of using more fatty acid than glucose to meet their bioenergetic demands. The present study was designed to evaluate the involvement of hexokinase and CPT-1 in the cell growth and proliferation of human prostate cancer cell lines, PC3, and LNCaP-FGC-10. Hexokinase and CPT-1 activities were examd. in the presence of different concns. of their inhibitors, lonidamine and etomoxir, to find the concn. of max. inhibition ([Imax]). To assess cell viability and proliferation, dimethylthiazol (MTT) assay was carried out using [Imax] for 24, 48, and 72 h on PC3 and LNCaP cells. Apoptosis was detd. using annexin-V, caspase-3 activity assay, Hoechst 33258 staining, and evaluation of mitochondrial membrane potential (MMP). Moreover, ATP levels were measured following lonidamine and etomoxir exposure. In addn., to define the impact of exogenous fatty acid on the cell growth and proliferation, CPT-1 activity was evaluated in the presence of palmitate (50 μM). Hexokinase and CPT-1 activities were significantly inhibited by lonidamine [600 μM] and etomoxir [100 μM] in both cell lines. Treatment of the cells with lonidamine [600 μM] resulted in a significant ATP redn., cell viability and apoptosis, caspase-3 activity elevation, MMP redn., and appearance of apoptosis-related morphol. changes in the cells. In contrast, etomoxir [100 μM] just decreased ATP levels in both cell lines without significant cell death and apoptosis. Compared with glucose (2 g/L), palmitate intensified CPT-1 activity in both cell lines, esp. in LNCaP cells. In addn., activity of CPT-1 was higher in LNCaP than PC3 cells. Our results suggest that prostate cancer cells may metabolize glucose as a source of bioenergetic pathways. ATP could also be produced by long-chain fatty acid oxidn. In addn., these data might suggest that LNCaP is more compatible with palmitate.
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  5. 5
    Nancolas, B.; Guo, L.; Zhou, R.; Nath, K.; Nelson, D. S.; Leeper, D. B.; Blair, I. A.; Glickson, J. D.; Halestrap, A. P. The anti-tumour agent lonidamine is a potent inhibitor of the mitochondrial pyruvate carrier and plasma membrane monocarboxylate transporters. Biochem. J. 2016, 473, 929– 936,  DOI: 10.1042/bj20151120
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    5
    The anti-tumour agent lonidamine is a potent inhibitor of the mitochondrial pyruvate carrier and plasma membrane monocarboxylate transporters
    Nancolas, Bethany; Guo, Lili; Zhou, Rong; Nath, Kavindra; Nelson, David S.; Leeper, Dennis B.; Blair, Ian A.; Glickson, Jerry D.; Halestrap, Andrew P.
    Biochemical Journal (2016), 473 (7), 929-936CODEN: BIJOAK; ISSN:0264-6021. (Portland Press Ltd.)
    Lonidamine (LND) is an anti-tumor drug particularly effective at selectively sensitizing tumors to chemotherapy, hyperthermia and radiotherapy, although its precise mode of action remains unclear. It has been reported to perturb the bioenergetics of cells by inhibiting glycolysis and mitochondrial respiration, whereas indirect evidence suggests it may also inhibit L-lactic acid efflux from cells mediated by members of the proton-linked monocarboxylate transporter (MCT) family and also pyruvate uptake into the mitochondria by the mitochondrial pyruvate carrier (MPC). In the present study, we test these possibilities directly. We demonstrate that LND potently inhibits MPC activity in isolated rat liver mitochondria (Ki 2.5 μM) and co-operatively inhibits L-lactate transport by MCT1, MCT2 and MCT4 expressed in Xenopus laevis oocytes with K0.5 and Hill coeff. values of 36-40 μM and 1.65-1.85 resp. In rat heart mitochondria LND inhibited the MPC with similar potency and uncoupled oxidn. of pyruvate was inhibited more effectively (IC50 ∼ 7 μM) than other substrates including glutamate (IC50 ∼ 20 μM). In isolated DB-1 melanoma cells 1-10 μM LND increased L-lactate output, consistent with MPC inhibition, but higher concns. (150 μM) decreased L-lactate output whereas increasing intracellular [L-lactate] > 5-fold, consistent with MCT inhibition. We conclude that MPC inhibition is the most sensitive anti-tumor target for LND, with addnl. inhibitory effects on MCT-mediated L-lactic acid efflux and glutamine/glutamate oxidn. Together these actions can account for published data on the selective tumor effects of LND on L-lactate, intracellular pH (pHi) and ATP levels that can be partially mimicked by the established MPC and MCT inhibitor α-cyano-4-hydroxycinnamate (CHC).
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  6. 6
    Nath, K.; Nelson, D. S.; Heitjan, D. F.; Leeper, D. B.; Zhou, R.; Glickson, J. D. Lonidamine induces intracellular tumor acidification and ATP depletion in breast, prostate and ovarian cancer xenografts and potentiates response to doxorubicin. NMR Biomed. 2015, 28, 281– 290,  DOI: 10.1002/nbm.3240
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    6
    Lonidamine induces intracellular tumor acidification and ATP depletion in breast, prostate and ovarian cancer xenografts and potentiates response to doxorubicin
    Nath, Kavindra; Nelson, David S.; Heitjan, Daniel F.; Leeper, Dennis B.; Zhou, Rong; Glickson, Jerry D.
    NMR in Biomedicine (2015), 28 (3), 281-290CODEN: NMRBEF; ISSN:0952-3480. (John Wiley & Sons Ltd.)
    We demonstrate that the effects of lonidamine (LND, 100 mg/kg, i.p.) are similar for a no. of xenograft models of human cancer including DB-1 melanoma and HCC1806 breast, BT-474 breast, LNCaP prostate and A2870 ovarian carcinomas. Following treatment with LND, each of these tumors exhibits a rapid decrease in intracellular pH, a small decrease in extracellular pH, a concomitant monotonic decrease in nucleoside triphosphate and an increase in inorg. phosphate over a 2-3 h period. We have previously demonstrated that selective intracellular tumor acidification potentiates response of this melanoma model to melphalan (7.5 mg/kg, i.v.), producing an estd. 89% cell kill based on tumor growth delay anal. We now show that, in both DB-1 melanoma and HCC1806 breast carcinoma, LND potentiates response to doxorubicin, producing 95% cell kill in DB-1 melanoma at 7.5 mg/kg, i.v. doxorubicin and 98% cell kill at 10.0 mg/kg doxorubicin, and producing a 95% cell kill in HCC1806 breast carcinoma at 12.0 mg/kg doxorubicin. Potentiation of doxorubicin may result from cation trapping of the weakly basic anthracycline. Recent experience with the clin. treatment of melanoma and other forms of human cancer suggests that these diseases will probably not be cured by a single therapeutic procedure other than surgery. A multimodality therapeutic approach will be required. As a potent modulator of tumor response to N-mustards and anthracyclines as well as tumor thermo- and radiosensitivity, LND promises to play an important clin. role in the management and possible complete local control of a no. of prevalent forms of human cancer. Copyright © 2014 John Wiley & Sons, Ltd.
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  7. 7
    Ravagnan, L.; Marzo, I.; Costantini, P.; Susin, S. A.; Zamzami, N.; Petit, P. X.; Hirsch, F.; Goulbern, M.; Poupon, M.-F.; Miccoli, L.; Xie, Z.; Reed, J. C.; Kroemer, G. Lonidamine triggers apoptosis via a direct, Bcl-2-inhibited effect on the mitochondrial permeability transition pore. Oncogene 1999, 18, 2537– 2546,  DOI: 10.1038/sj.onc.1202625
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    7
    Lonidamine triggers apoptosis via a direct, Bcl-2-inhibited effect on the mitochondrial permeability transition pore
    Ravagnan, Luigi; Marzo, Isabel; Costantini, Paola; Susin, Santos A.; Zamzami, Naoufal; Petit, Patrice X.; Hirsch, Franqois; Goulbern, Marc; Poupon, Marie-France; Miccoli, Laurent; Xie, Zhihua; Reed, John C.; Kroemer, Guido
    Oncogene (1999), 18 (16), 2537-2546CODEN: ONCNES; ISSN:0950-9232. (Stockton Press)
    The mol. mode of action of lonidamine, a therapeutic agent employed in cancer chemotherapy, has been elusive. Here we provide evidence that lonidamine (LND) acts on mitochondria to induce apoptosis. LND provokes a disruption of the mitochondrial transmembrane potential which precedes signs of nuclear apoptosis and cytolysis. The mitochondrial and cytocidal effects of LND are not prevented by inhibitors of caspases or of mRNA or protein synthesis. However, they are prevented by transfection-enforced overexpression of Bcl-2, an oncoprotein which inhibits apoptosis by stabilizing the mitochondrial membrane barrier function. Accordingly, the cell death-inducing effect of LND is amplified by simultaneous addn. of PK11195, an isoquinoline ligand of the peripheral benzodiazepine receptor which antagonizes the cytoprotective effect of Bcl-2. When added to isolated nuclei, LND fails to provoke DNA degrdn. unless mitochondria are added simultaneously. In isolated mitochondria, LND causes the dissipation of the mitochondrial inner transmembrane potential and the release of apoptogenic factors capable of inducing nuclear apoptosis in vitro. Thus the mitochondrion is the subcellular target of LND. All effects of LND on isolated mitochondria are counteracted by cyclosporin A, an inhibitor of the mitochondrial PT pore. We therefore tested the effect of LND on the purified PT pore reconstituted into liposomes. LND permeabilizes liposomal membranes contg. the PT pore. This effect is prevented by addn. of recombinant Bcl-2 protein but not by a mutant Bcl-2 protein that has lost its apoptosis-inhibitory function. Altogether these data indicate that LND represents a novel type of anti-cancer agent which induces apoptosis via a direct effect on the mitochondrial PT pore.
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  8. 8
    Crompton, M. The mitochondrial permeability transition pore and its role in cell death. Biochem. J. 1999, 341, 233– 249,  DOI: 10.1042/bj3410233
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    8
    The mitochondrial permeability transition pore and its role in cell death
    Crompton, Martin
    Biochemical Journal (1999), 341 (2), 233-249CODEN: BIJOAK; ISSN:0264-6021. (Portland Press Ltd.)
    A review, with ∼208 refs. This article reviews the involvement of the mitochondrial permeability transition pore in necrotic and apoptotic cell death. The pore is formed from a complex of the voltage-dependent anion channel (VDAC), the adenine nucleotide translocase and cyclophilin-D (CyP-D) at contact sites between the mitochondrial outer and inner membranes. In vitro, under pseudopathol. conditions of oxidative stress, relatively high Ca2+ and low ATP, the complex flickers into an open-pore state allowing free diffusion of low-Mr solutes across the inner membrane. These conditions correspond to those that unfold during tissue ischemia and reperfusion, suggesting that pore opening may be an important factor in the pathogenesis of necrotic cell death following ischemia/reperfusion. Evidence that the pore does open during ischemia/reperfusion is discussed. There are also strong indications that the VDAC-adenine nucleotide translocase-CyP-D complex can recruit a no. of other proteins, including Bax, and that the complex is utilized in some capacity during apoptosis. The apoptotic pathway is amplified by the release of apoptogenic proteins from the mitochondrial inter-membrane space, including cytochrome c, apoptosis-inducing factor and some procaspases. Current evidence that the pore complex is involved in outer-membrane rupture and release of these proteins during programmed cell death is reviewed, along with indications that transient pore opening may provoke "accidental" apoptosis.
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  9. 9
    Rosbe, K. W.; Brann, T. W.; Holden, S. A.; Teicher, B. A.; Frei, E. Effect of Lonidamine on the cytotoxicity of four alkylating agents in vitro. Cancer Chemother. Pharmacol. 1989, 25, 32– 36,  DOI: 10.1007/bf00694335
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    9
    Effect of lonidamine on the cytotoxicity of four alkylating agents in vitro
    Rosbe, Kristina W.; Brann, Terrence W.; Holden, Sylvia A.; Teicher, Beverly A.; Frei, Emil, III
    Cancer Chemotherapy and Pharmacology (1989), 25 (1), 32-6CODEN: CCPHDZ; ISSN:0344-5704.
    The authors examd. the ability of lonidamine, which has been described as an inhibitor of cellular respiration and glycolysis, to enhance the cytotoxicity of alkylating agents to MCF-7 human breast carcinoma cells. Lonidamine was increasingly cytotoxic to MCF-7 cells with increasing time of exposure. With a 12-h exposure, the IC50 for lonidamine was about 365 μM, and with a 24-h exposure it was about 170 μM. A drug concn. of 250 μM was chosen for use in the drug combination studies. Lonidamine appeared to have a dose-modifying effect on cisplatin (CDDP), producing increasingly supraadditive cell kill with increasing CDDP concn. Lonidamine also appeared to have a dose-modifying effect on melphalan cytotoxicity in the melphalan concn. range of 100-500 μM. At concns of 10-100 μM melphalan, the drug combination survival after 1 h exposure fell within the envelope of additivity for the 2 agents. However, maintaining the presence of lonidamine for an addnl. 12 h increased the effect such that the combination was supraadditive over the entire concn. range of melphalan. Simultaneous exposure to 4-hydroperoxycyclophosphamide (4-HC) and lonidamine for 1 h resulted in greater that additive cell kill, and extending the lonidamine exposure period such that lonidamine was present during and 12 h after 4-HC treatment further increased this effect. Lonidamine had a moderate effect of the cytotoxicity of carmustine (BCNU) with a 1 h simultaneous exposure; however, this treatment combination reached greater than additive cytotoxicity only at the highest concn. of BCNU tested. Extending the lonidamine exposure time for an addnl. 12 h resulted in supraaditive cell kill over the BCNU concn. range. Therefore, when lonidamine was present during exposure to the alkylating agent and its presence was then extended for an addnl. 12 h, a synergistic cell kill was produced with all 4 alkylating agents tested.
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  10. 10
    Angioli, R.; Janicek, M.; Sevin, B.; Estape, R.; Averette, H.; Koechli, O.; Untch, M.; Penalver, M. Use of lonidamine to potentiate the effect of cisplatin and carboplatin on platinum resistant human ovarian cancer cells. Internet J. Oncol. 1997, 11, 777– 780,  DOI: 10.3892/ijo.11.4.777
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    Chen, H.; Chen, F.; Hu, W.; Gou, S. Effective platinum(IV) prodrugs conjugated with lonidamine as a functional group working on the mitochondria. J. Inorg. Biochem. 2018, 180, 119– 128,  DOI: 10.1016/j.jinorgbio.2017.11.017
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    11
    Effective platinum(IV) prodrugs conjugated with lonidamine as a functional group working on the mitochondria
    Chen, Hong; Chen, Feihong; Hu, Weiwei; Gou, Shaohua
    Journal of Inorganic Biochemistry (2018), 180 (), 119-128CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier)
    Platinum-based anticancer drugs are one of the most widely used anticancer chemotherapeutics in oncol. Lonidamine (LND) could increase the response of human tumor cells to platinum(II) drugs in preclin. studies by working on the mitochondria. Herein, five platinum(IV) prodrugs conjugated with their potentiator LND are prepd., and most of the target complexes achieve improved anticancer activities compared with their platinum(II) precursors. Notably, Pt(NH3)2(LND)Cl3 (complex 1) derived from cisplatin achieve significantly improved anticancer activities against LNCaP cells and could trigger cancer cell death via an apoptotic pathway and the cell cycle arrest mainly at S phases. And the induction of apoptosis by complex 1 in LNCaP cells is closely assocd. with mitochondrial function disruption and reactive oxygen species (ROS) accumulation. Moreover, it is possessed of the ability to overcome cisplatin-resistance. Further research revealed that complex 1 could be easily reduced to release its platinum(II) precursor and axial ligand by ascorbic acid. All the results provide evidence to support the design strategy of conjugating platinum complexes with its potentiator to improve their anticancer effect.
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  12. 12
    Okulova, Y. N.; Zenin, I. V.; Shutkov, I. A.; Kirsanov, K. I.; Kovaleva, O. N.; Lesovaya, E. A.; Fetisov, T. I.; Milaeva, E. R.; Nazarov, A. A. Antiproliferative activity of Pt(IV) complexes with lonidamine and bexarotene ligands attached via succinate-ethylenediamine linker. Inorg. Chim. Acta 2019, 495, 119010,  DOI: 10.1016/j.ica.2019.119010
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    12
    Antiproliferative activity of Pt(IV) complexes with lonidamine and bexarotene ligands attached via succinate-ethylenediamine linker
    Okulova, Y. N.; Zenin, I. V.; Shutkov, I. A.; Kirsanov, K. I.; Kovaleva, O. N.; Lesovaya, E. A.; Fetisov, T. I.; Milaeva, E. R.; Nazarov, A. A.
    Inorganica Chimica Acta (2019), 495 (), 119010CODEN: ICHAA3; ISSN:0020-1693. (Elsevier B.V.)
    The authors present the synthesis and cytotoxic potencies of new Pt(IV) complexes with lonidamine and bexarotene ligand tethered to Pt-center via a succinate-ethylenediamine linker. The in vitro results for a series of complexes with cisplatin, dichloride(ethane-1,2-diamine)platinum(II), or oxaliplatin core indicate that the addn. to the structure lonidamine or bexarotene moiety can confer activity or selectivity of Pt(IV) complexes.
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  13. 13
    Nosova, Y. N.; Foteeva, L. S.; Zenin, I. V.; Fetisov, T. I.; Kirsanov, K. I.; Yakubovskaya, M. G.; Antonenko, T. A.; Tafeenko, V. A.; Aslanov, L. A.; Lobas, A. A.; Gorshkov, M. V.; Galanski, M.; Keppler, B. K.; Timerbaev, A. R.; Milaeva, E. R.; Nazarov, A. A. Enhancing the Cytotoxic Activity of Anticancer Pt IV Complexes by Introduction of Lonidamine as an Axial Ligand. Eur. J. Med. Chem. 2017, 2017, 1785– 1791,  DOI: 10.1002/ejic.201600857
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  14. 14
    Ruttala, H. B.; Ramasamy, T.; Poudel, B. K.; Ruttala, R. R. T.; Jin, S. G.; Choi, H.-G.; Ku, S.-K.; Yong, C. S.; Kim, J. O. Multi-responsive albumin-lonidamine conjugated hybridized gold nanoparticle as a combined photothermal-chemotherapy for synergistic tumor ablation. Acta Biomater. 2020, 101, 531– 543,  DOI: 10.1016/j.actbio.2019.11.003
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    14
    Multi-responsive albumin-lonidamine conjugated hybridized gold nanoparticle as a combined photothermal-chemotherapy for synergistic tumor ablation
    Ruttala, Hima Bindu; Ramasamy, Thiruganesh; Poudel, Bijay Kumar; Ruttala, Raghu Ram Teja; Jin, Sung Giu; Choi, Han-Gon; Ku, Sae-Kwang; Yong, Chul Soon; Kim, Jong Oh
    Acta Biomaterialia (2020), 101 (), 531-543CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)
    Herein, we developed a multifunctional nanoplatform based on the nanoassembly of gold nanoparticles (GNP) conjugated with lonidamine (LND) and aptamer AS1411 (AS-LAGN) as an effective cancer treatment. Conjugating AS1411 aptamer on the surface of the nanoparticle significantly improved particle accumulation in cancer cells via specific affinity toward the nucleolin receptors. In vitro study clearly revealed that laser irradn.-based hyperthermia effect enhanced the chemotherapeutic effects of LND. Combinational treatment modalities revealed significant apoptosis with higher cell killing effect due to increased ROS prodn. and inhibition of cell migration. GNP's ability to convert the excited state photon energy into thermal heat enabled synergistic photothermal/chemotherapy with improved therapeutic efficacy in animal models. Moreover, immunohistochem. staining assays confirmed the ability of AS-LAGN to induce cellular apoptosis/necrosis and ablation in tumor tissues, without causing evident damages to the surrounding healthy tissues. Altogether, this AS-LAGN nanoplatform could be a promising strategy for mitochondria-based cancer treatment. We have designed a facile biodegradable multifunctional nanocarrier system to target the mitochondria, the major "power house" of the cancer cells. We have constructed a multifunctional nanoassembly of protein coronated gold nanoparticles (GNP) conjugated with lonidamine (LND) and aptamer AS1411 (AS-LAGN) as an effective combination of phototherapy with chemotherapy for cancer treatment. The LND was conjugated with albumin which was in turn conjugated to GNP via redox-liable disulfide linkage to generate oxidative stress and ROS to kill cancer cells. Consistently, AS-LAGN showed enhanced antitumor efficacy in xenograft tumor model with remarkable tumor regression property.
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  15. 15
    Qin, Q.-P.; Liu, Y.-C.; Wang, H.-L.; Qin, J.-L.; Cheng, F.-J.; Tang, S.-F.; Liang, H. Synthesis and antitumor mechanisms of a copper(ii) complex of anthracene-9-imidazoline hydrazone (9-AIH). Metallomics 2015, 7, 1124– 1136,  DOI: 10.1039/C5MT00027K
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    15
    Synthesis and antitumor mechanisms of a copper(II) complex of anthracene-9-imidazoline hydrazone (9-AIH)
    Qin, Qi-Pin; Liu, Yan-Cheng; Wang, Hai-Lu; Qin, Jiao-Lan; Cheng, Feng-Jie; Tang, Shang-Feng; Liang, Hong
    Metallomics (2015), 7 (7), 1124-1136CODEN: METAJS; ISSN:1756-591X. (Royal Society of Chemistry)
    A new anthracycline deriv., anthracene-9-imidazoline hydrazone (9-AIH), was synthesized and selected as an antitumor ligand to afford a copper(II) complex of 9-AIH, cis-[CuIICl2(9-AIH)] (1). Complex 1 was structurally characterized by IR, elemental anal., ESI-MS and single crystal X-ray diffraction anal. By MTT assay, it was revealed that 1 showed overall a higher in vitro cytotoxicity than 9-AIH towards a panel of human tumor cell lines, with IC50 values from 0.94-3.68 μM, in which the BEL-7404 cell line was the most sensitive to 1. By spectral analyses and gel electrophoresis, the DNA binding affinity of 9-AIH and 1 was detd. 9-AIH was suggested to bind with DNA in an intercalative mode, with a quenching const. of 1.04 × 104 M-1 on the EB-DNA complex. While for 1, both intercalative and covalent binding modes were suggested. By flow cytometry, 1 was found to block the cell cycle of BEL-7404 cells in a dose-dependent mode, in which it induced the G2/M phase arrest at 0.5 μM and induced the S phase arrest at higher concns. of 1.0 or 2.0 μM. From the cellular morphol. observations under different fluorescence probe staining, a dose-dependent manner of 1 to induce cell apoptosis in the late stage was suggested. Comparatively, equiv. apoptotic cells, resp., in the early and late stages were found when incubated with 2.0 μM of 9-AIH. The mitochondrial membrane potential measured by JC-1 staining and the ROS generation in cells detected using a DCFH-DA probe suggested that the cell apoptosis induced by 1 might undergo the ROS-related mitochondrial pathway. Accordingly, the mutant p53 expression was found to be suppressed and the caspase cascade (caspase-9/3) was consequently activated by 1. This action mechanism for 1 in the BEL-7404 cells was unique and was not found in the presence of 9-AIH under the same conditions, indicating their different antitumor mechanism. Furthermore, the in vivo acute toxicity of 1 tested on mice indicated that 1 should be a high cytotoxic antitumor agent, with the LD50 value in the range of 32-45 mg kg-1, which is much higher than that of 9-AIH. From the above results, the central Cu(II) of 1 in the coordinated mode with 9-AIH was believed to play a key role in exerting both the high cytotoxicity and the effective antitumor mechanism.
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  16. 16
    Raman, N.; Jeyamurugan, R.; Senthilkumar, R.; Rajkapoor, B.; Franzblau, S. G. In vivo and in vitro evaluation of highly specific thiolate carrier group copper(II) and zinc(II) complexes on Ehrlich ascites carcinoma tumor model. Eur. J. Med. Chem. 2010, 45, 5438– 5451,  DOI: 10.1016/j.ejmech.2010.09.004
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    16
    In vivo and in vitro evaluation of highly specific thiolate carrier group copper(II) and zinc(II) complexes on Ehrlich ascites carcinoma tumor model
    Raman, N.; Jeyamurugan, R.; Senthilkumar, R.; Rajkapoor, B.; Franzblau, Scott G.
    European Journal of Medicinal Chemistry (2010), 45 (11), 5438-5451CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
    A new series of copper(II) and zinc(II) benzene-1,2-dithiol complexes with novel Schiff base ligands have been prepd. The Schiff base ligands are derived from the reaction of 3-(3-phenyl-allylidene)-pentane-2,4-dione with para substituted aniline. Their structures have been established by anal. and spectral data. The higher ε and low A‖ values together with pos. redn. potentials for these copper complexes suggest that they can mimic the functional properties of naturally occurring proteins. In vivo and in vitro antitumor functions of the complexes against Ehrlich ascites carcinoma tumor model have been studied. The min. inhibitory concn. of the complexes has also been studied against Mycobacterium tuberculosis strain H37Rv. These complexes exhibit significant antitumor, cytotoxic and antituberculosis activity.
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  17. 17
    Palanimuthu, D.; Shinde, S. V.; Somasundaram, K.; Samuelson, A. G. In Vitro and in Vivo Anticancer Activity of Copper Bis(thiosemicarbazone) Complexes. J. Med. Chem. 2013, 56, 722– 734,  DOI: 10.1021/jm300938r
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    17
    In Vitro and in Vivo Anticancer Activity of Copper Bis(thiosemicarbazone) Complexes
    Palanimuthu, Duraippandi; Shinde, Sridevi Vijay; Somasundaram, Kumaravel; Samuelson, Ashoka G.
    Journal of Medicinal Chemistry (2013), 56 (3), 722-734CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Neutral and cationic copper bis(thiosemicarbazone) complexes bearing Me, Ph, and H, on the diketo-backbone of the ligand were synthesized. All of them were characterized by spectroscopic methods and in three cases by x-ray crystallog. In vitro cytotoxicity studies revealed that they are cytotoxic, unlike the corresponding Zn complexes. Copper complexes Cu(GTSC) and Cu(GTSCHCl) derived from glyoxal bis(4-methyl-4-phenyl-3-thiosemicarbazone) (GTSCH2) are the most cytotoxic complexes against various human cancer cell lines, with a potency similar to that of the anticancer drug adriamycin and up to 1000 fold higher than that of the corresponding Zn complex. Tritiated thymidine incorporation assay revealed that Cu(GTSC) and Cu(GTSCHCl) inhibit DNA synthesis substantially. Cell cycle analyses showed that Cu(GTSC) and Cu(GTSCHCl) induce apoptosis in HCT116 cells. The Cu(GTSCHCl) complex caused distinct DNA cleavage and Topo IIα inhibition unlike that for Cu(GTSC). In vivo administration of Cu(GTSC) significantly inhibits tumor growth in HCT116 xenografts in nude mice.
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    Montagner, D.; Fresch, B.; Browne, K.; Gandin, V.; Erxleben, A. A Cu(ii) complex targeting the translocator protein: in vitro and in vivo antitumor potential and mechanistic insights. Chem. Commun. 2017, 53, 134– 137,  DOI: 10.1039/C6CC08100B
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    A Cu(II) complex targeting the translocator protein: in vitro and in vivo antitumor potential and mechanistic insights
    Montagner, D.; Fresch, B.; Browne, K.; Gandin, V.; Erxleben, A.
    Chemical Communications (Cambridge, United Kingdom) (2017), 53 (1), 134-137CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    A new Cu-based anticancer metallodrug which targets the translocator protein is reported. [CuBr2(TZ6)] elicits a remarkable in vitro cytotoxicity in sensitive and multidrug resistant cell lines and induces a 98% redn. of tumor mass in a murine tumor model. Target binding was studied by exptl. and computational methods.
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  19. 19
    Laws, K.; Bineva-Todd, G.; Eskandari, A.; Lu, C.; O’Reilly, N.; Suntharalingam, K. A Copper(II) Phenanthroline Metallopeptide That Targets and Disrupts Mitochondrial Function in Breast Cancer Stem Cells. Angew. Chem., Int. Ed. 2018, 57, 287– 291,  DOI: 10.1002/ange.201710910
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    19
    A Copper(II) Phenanthroline Metallopeptide That Targets and Disrupts Mitochondrial Function in Breast Cancer Stem Cells
    Laws, Kristine; Bineva-Todd, Ganka; Eskandari, Arvin; Lu, Chunxin; O'Reilly, Nicola; Suntharalingam, Kogularamanan
    Angewandte Chemie, International Edition (2018), 57 (1), 287-291CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The breast cancer stem cell (CSC) and bulk breast cancer cell potency of a series of metallopeptides contg. dichloro(1,10-phenanthroline)copper(II) and various organelle-targeting peptide sequences is reported. The mitochondria-targeting metallopeptide 1 exploits the higher mitochondrial load in breast CSCs over the corresponding non-CSCs and the vulnerability of breast CSCs to mitochondrial damage to potently and selectively kill breast CSCs. Strikingly, 1 reduces the formation and size of mammospheres to a greater extent than salinomycin, an established CSC-potent agent. Mechanistic studies show that 1 enters CSC mitochondria, induces mitochondrial dysfunction, generates reactive oxygen species (ROS), activates JNK and p38 pathways, and prompts apoptosis. To the best of our knowledge, 1 is the first metallopeptide to selectivity kill breast CSCs in vitro.
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  20. 20
    Mahendiran, D.; Kumar, R. S.; Viswanathan, V.; Velmurugan, D.; Rahiman, A. K. In vitro and in vivo anti-proliferative evaluation of bis(4′-(4-tolyl)-2,2′:6′,2″-terpyridine)copper(II) complex against Ehrlich ascites carcinoma tumors. JBIC, J. Biol. Inorg. Chem. 2017, 22, 1109– 1122,  DOI: 10.1007/s00775-017-1488-6
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    20
    In vitro and in vivo anti-proliferative evaluation of bis(4'-(4-tolyl)-2,2':6',2''-terpyridine)copper(II) complex against Ehrlich ascites carcinoma tumors
    Mahendiran, Dharmasivam; Kumar, Raju Senthil; Viswanathan, Vijayan; Velmurugan, Devadasan; Rahiman, Aziz Kalilur
    JBIC, Journal of Biological Inorganic Chemistry (2017), 22 (7), 1109-1122CODEN: JJBCFA; ISSN:0949-8257. (Springer)
    The bis(4'-(4-tolyl)-2,2':6',2''-terpyridine)copper(II) complex [Cu(ttpy)2]Cl2 was synthesized and authenticated by single crystal anal., which shows distorted octahedral geometry around copper(II) ion. The crystal packing is stabilized by C-H···π inter and intramol. interactions. The complex was found to be lipophilic as detd. by shake-flask method. In vitro cytotoxicity of the complex was tested against Ehrlich ascites carcinoma (EAC) and L6 myotube cell lines. The complex exhibit potent cytotoxicity with respect to the com. available anticancer drug cisplatin. Hoechst 33258, AO/EB and PI (flow cytometry) staining methods suggest that the complex can induce apoptosis in EAC cells. Cell cycle analyses also support the induced apoptosis. Cellular uptake studies revealed that the complex can go into the cytoplasm and accumulate in the cell nuclei. The complex induces EAC cell apoptosis through a ROS-mediated mitochondrial pathway by activating caspase 3 and caspase 7 and regulates the Bcl-2 family proteins. In vivo study of the complex was validated against the animal tumor growth (EAC) cell in Swiss albino mice.
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  21. 21
    Becco, L.; García-Ramos, J. C.; Azuara, L. R.; Gambino, D.; Garat, B. Analysis of the DNA Interaction of Copper Compounds Belonging to the Casiopeínas Antitumoral Series. Biol. Trace Elem. Res. 2014, 161, 210– 215,  DOI: 10.1007/s12011-014-0098-1
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    21
    Analysis of the DNA Interaction of Copper Compounds Belonging to the Casiopei´nas Antitumoral Series
    Becco, Lorena; Garcia-Ramos, Juan Carlos; Azuara, Lena Ruiz; Gambino, Dinorah; Garat, Beatriz
    Biological Trace Element Research (2014), 161 (2), 210-215CODEN: BTERDG; ISSN:0163-4984. (Springer)
    Casiopei´nas are mixed-chelate copper complexes with antitumor tested potential. Their activity, both in vitro and in vivo, as antiproliferative, cytotoxic, and genotoxic drugs has been assessed. Biol. results of these copper compds. have deserved some of them entering clin. trials. Significant efforts have been devoted to the in-depth identification of their mechanism of action. Using gel electrophoresis anal., we have previously shown that the interaction of the Casiopei´nas Cas II-gly, [Cu(4,7-dimethyl-1,10-phenanthroline)(glycinate)]NO3 with DNA, triggers the cleavage of the biomol. by a free radical mechanism. In this work, we further study the behavior of different complexes of the same Casiopei´nas series also including glycinate as co-ligand {Cas VI-gly (5,6 dimethyl-1,10-phenanthroline glycinato copper(II) nitrate), Cas VII-gly (1,10-phenanthroline glycinato copper(II) nitrate), and Cas IX-gly (2,2'-bipyridine glycinato copper(II) nitrate)} and of a Casiopei´nas with a different co-ligand (Cas III-Cs; 4,7-dimethyl-1,10-phenanthroline salicylaldehydato-copper(II) nitrate). While all of them produce DNA degrdn., the performance in the presence of a radical scavenger suggests the existence of differences in their mechanism of interaction with DNA.
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  22. 22
    Gandin, V.; Ceresa, C.; Esposito, G.; Indraccolo, S.; Porchia, M.; Tisato, F.; Santini, C.; Pellei, M.; Marzano, C. Therapeutic potential of the phosphino Cu(I) complex (HydroCuP) in the treatment of solid tumors. Sci. Rep. 2017, 7, 13936,  DOI: 10.1038/s41598-017-13698-1
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    Therapeutic potential of the phosphino Cu(I) complex (HydroCuP) in the treatment of solid tumors
    Gandin Valentina; Marzano Cristina; Ceresa Cecilia; Esposito Giovanni; Indraccolo Stefano; Porchia Marina; Tisato Francesco; Santini Carlo; Pellei Maura
    Scientific reports (2017), 7 (1), 13936 ISSN:.
    [Cu(thp)4][PF6] (HydroCuP) is a phosphino copper(I) complex highly soluble and stable in physiological media that has been developed as a possible viable alternative to platinum-based drugs for anticancer therapy. HydroCuP potently inhibited the growth of human cancer cells derived from solid tumors by inducing endoplasmatic reticulum (ER) stress thus leading to cell death through paraptosis with a preferential efficacy against cancer rather than non-cancer cells. Aim of the present study was to assess the therapeutic potential of HydroCuP in vivo, in syngenic and xenograft murine models of solid tumors by triggering the Unfolded Protein Response (UPR) pathway. With respect to platinum drugs, HydroCuP induced a markedly higher reduction of tumor growth associated with minimal animal toxicity. In human colorectal cancer xenografts, chemotherapy with HydroCuP was extremely effective in both oxaliplatin-sensitive and resistant models. The favorable in vivo tolerability of HydroCuP was also correlated to an encouraging biodistribution profile. Additionally, no signs of drug-related neurotoxicity and nephrotoxicity were observed. Altogether, these results demonstrate that HydroCuP appears worth of further investigation to evaluate its therapeutic activity towards a broad spectrum of solid malignancies.
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    Gandin, V.; Pellei, M.; Tisato, F.; Porchia, M.; Santini, C.; Marzano, C. A novel copper complex induces paraptosis in colon cancer cells via the activation of ER stress signalling. J. Cell. Mol. Med. 2012, 16, 142– 151,  DOI: 10.1111/j.1582-4934.2011.01292.x
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    23
    A novel copper complex induces paraptosis in colon cancer cells via the activation of ER stress signalling
    Gandin, Valentina; Pellei, Maura; Tisato, Francesco; Porchia, Marina; Santini, Carlo; Marzano, Cristina
    Journal of Cellular and Molecular Medicine (2012), 16 (1), 142-151CODEN: JCMMC9; ISSN:1582-4934. (Wiley-Blackwell)
    Platinum anticancer drugs have been used for three decades despite their serious side effects and the emerging of resistance phenomena. Recently, a phosphine copper(I) complex, [Cu(thp)4][PF6] (CP), gained special attention because of its strong antiproliferative effects. CP killed human colon cancer cells more efficiently than cisplatin and oxaliplatin and it overcame platinum drug resistance. CP preferentially reduced cancer cell viability whereas non-tumor cells were poorly affected. Colon cancer cells died via a programmed cell death whose transduction pathways were characterized by the absence of hallmarks of apoptosis. The inhibition of 26S proteasome activities induced by CP caused intracellular accumulation of polyubiquitinated proteins and the functional suppression of the ubiquitin-proteasome pathway thus triggering endoplasmic reticulum stress. These data, providing a mechanistic characterization of CP-induced cancer cell death, shed light on the signaling pathways involved in paraptosis thus offering a new tool to overcome apoptosis-resistance in colon cancer cells.
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    Gandin, V.; Tisato, F.; Dolmella, A.; Pellei, M.; Santini, C.; Giorgetti, M.; Marzano, C.; Porchia, M. In Vitro and in Vivo Anticancer Activity of Copper(I) Complexes with Homoscorpionate Tridentate Tris(pyrazolyl)borate and Auxiliary Monodentate Phosphine Ligands. J. Med. Chem. 2014, 57, 4745– 4760,  DOI: 10.1021/jm500279x
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    24
    In Vitro and in Vivo Anticancer Activity of Copper(I) Complexes with Homoscorpionate Tridentate Tris(pyrazolyl)borate and Auxiliary Monodentate Phosphine Ligands
    Gandin, Valentina; Tisato, Francesco; Dolmella, Alessandro; Pellei, Maura; Santini, Carlo; Giorgetti, Marco; Marzano, Cristina; Porchia, Marina
    Journal of Medicinal Chemistry (2014), 57 (11), 4745-4760CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Tetrahedral copper(I) TpCuP complexes 1-15, where Tp is a N,N,N-tris(azolyl)borate and P is a tertiary phosphine, have been synthesized and characterized by NMR, ESI-MS, and XAS-EXAFS, and x-ray diffraction analyses on the representative complexes 1 and 10, resp. All copper(I) complexes were evaluated for their antiproliferative activity against a panel of human cancer cell lines (including cisplatin and multidrug-resistant sublines). The two most effective complexes [HB(pz)3]Cu(PCN), 1, and [HB(pz)3]Cu(PTA), 2, showed selectivity toward tumor vs normal cells, inhibition of 26S proteasome activity assocd. with endoplasmic reticulum (ER) stress, and unfolded protein response (UPR) activation. No biochem. hallmarks of apoptosis were detected, and morphol. studies revealed an extensive cytoplasmic vacuolization coherently with a paraptosis-like cell death mechanism. Finally, the antitumor efficacy of complex 1 was validated in the murine Lewis Lung Carcinoma (LLC) model.
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    Erxleben, A. Interactions of copper complexes with nucleic acids. Coord. Chem. Rev. 2018, 360, 92– 121,  DOI: 10.1016/j.ccr.2018.01.008
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    Interactions of copper complexes with nucleic acids
    Erxleben, Andrea
    Coordination Chemistry Reviews (2018), 360 (), 92-121CODEN: CCHRAM; ISSN:0010-8545. (Elsevier B.V.)
    A review. Covalent or non-covalent interactions with DNA are the basis for many potential biomedical applications of copper complexes, ranging from DNA structural probes and foot printing agents to anticancer drugs to gene delivery. Ideally, a complex binds selectively to a specific DNA sequence, conformation or higher order structure or causes a permanent structural transition or conformational change. The literature in this field has been constantly growing over the past two to three decades as new applications were emerging. This gives an overview of the state-of-the-art of DNA-binding Cu complexes designed for applications in bioinorg. and medicinal inorg. chem., with a focus on the most relevant ligand classes, i.e. amino acids and peptides, phenanthrolines and phenanthroline-like ligands, terpyridines, porphyrins, Schiff bases and (thio)semicarbazones, polyaza macrocycles and tripodal ligands.
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    Krasnovskaya, O.; Naumov, A.; Guk, D.; Gorelkin, P.; Erofeev, A.; Beloglazkina, E.; Majouga, A. Copper Coordination Compounds as Biologically Active Agents. Int. J. Mol. Sci. 2020, 21, 3965,  DOI: 10.3390/ijms21113965
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    Copper coordination compounds as biologically active agents
    Krasnovskaya, Olga; Naumov, Alexey; Guk, Dmitry; Gorelkin, Peter; Erofeev, Alexander; Beloglazkina, Elena; Majouga, Alexander
    International Journal of Molecular Sciences (2020), 21 (11), 3965CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)
    Copper-contg. coordination compds. attract wide attention due to the redox activity and biogenicity of copper ions, providing multiple pathways of biol. activity. The pharmacol. properties of metal complexes can be fine-tuned by varying the nature of the ligand and donor atoms. Copper-contg. coordination compds. are effective antitumor agents, constituting a less expensive and safer alternative to classical platinum-contg. chemotherapy, and are also effective as antimicrobial, antituberculosis, antimalarial, antifugal, and anti-inflammatory drugs. 64Cu-labeled coordination compds. are promising PET imaging agents for diagnosing malignant pathologies, including head and neck cancer, as well as the hallmark of Alzheimer's disease amyloid-β (Aβ). In this review article, we summarize different strategies for possible use of coordination compds. in the treatment and diagnosis of various diseases, and also various studies of the mechanisms of antitumor and antimicrobial action.
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    Kellett, A.; Molphy, Z.; McKee, V.; Slator, C. In Metal-based Anticancer Agents; Casini, A., Vessières, A., Meier-Menches, S. M., Eds.; The Royal Society of Chemistry, 2019; pp 91– 119.
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    Shao, S.; Si, J.; Shen, Y. Copper as the Target for Anticancer Nanomedicine. Adv. Ther. 2019, 2, 1800147,  DOI: 10.1002/adtp.201800147
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    Balsano, C.; Porcu, C.; Sideri, S. Is copper a new target to counteract the progression of chronic diseases?. Metallomics 2018, 10, 1712– 1722,  DOI: 10.1039/c8mt00219c
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    Is copper a new target to counteract the progression of chronic diseases?
    Balsano, Clara; Porcu, Cristiana; Sideri, Silvia
    Metallomics (2018), 10 (12), 1712-1722CODEN: METAJS; ISSN:1756-591X. (Royal Society of Chemistry)
    A review. Altered regulation of copper (Cu) homeostasis may contribute to the development of many pathologies, such as metabolic, cardiovascular, neurodegenerative and cancerous diseases. Cu serum concns. are strictly related to oxidative stress. During the past decade, it has been well demonstrated that even marginal deficits of this element contribute to development and progression of a no. of chronic diseases. On the other hand, an excess of Cu may become a potent oxidant causing the generation of reactive oxygen species (ROS) and leading to the formation of macromols. dangerous to health. In this review we will describe several chronic inflammatory diseases pathogenically related to the alteration of serum copper levels. Some considerations on present and future perspectives for use of natural antioxidants as effective drugs for the treatment of chronic diseases will be made to shed a glimmer of light on some of the mechanisms employed by natural antioxidants in controlling the distribution and concn. of biometals.
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    Denoyer, D.; Masaldan, S.; La Fontaine, S.; Cater, M. A. Targeting copper in cancer therapy: “Copper That Cancer”. Metallomics 2015, 7, 1459– 1476,  DOI: 10.1039/C5MT00149H
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    Targeting copper in cancer therapy: 'Copper That Cancer'
    Denoyer, Delphine; Masaldan, Shashank; La Fontaine, Sharon; Cater, Michael A.
    Metallomics (2015), 7 (11), 1459-1476CODEN: METAJS; ISSN:1756-591X. (Royal Society of Chemistry)
    Copper is an essential micronutrient involved in fundamental life processes that are conserved throughout all forms of life. The ability of copper to catalyze oxidn.-redn. (redox) reactions, which can inadvertently lead to the prodn. of reactive oxygen species (ROS), necessitates the tight homeostatic regulation of copper within the body. Many cancer types exhibit increased intratumoral copper and/or altered systemic copper distribution. The realization that copper serves as a limiting factor for multiple aspects of tumor progression, including growth, angiogenesis and metastasis, has prompted the development of copper-specific chelators as therapies to inhibit these processes. Another therapeutic approach utilizes specific ionophores that deliver copper to cells to increase intracellular copper levels. The therapeutic window between normal and cancerous cells when intracellular copper is forcibly increased, is the premise for the development of copper-ionophores endowed with anticancer properties. Also under investigation is the use of copper to replace platinum in coordination complexes currently used as mainstream chemotherapies. In comparison to platinum-based drugs, these promising copper coordination complexes may be more potent anticancer agents, with reduced toxicity toward normal cells and they may potentially circumvent the chemoresistance assocd. with recurrent platinum treatment. In addn., cancerous cells can adapt their copper homeostatic mechanisms to acquire resistance to conventional platinum-based drugs and certain copper coordination complexes can re-sensitize cancer cells to these drugs. This review will outline the biol. importance of copper and copper homeostasis in mammalian cells, followed by a discussion of our current understanding of copper dysregulation in cancer, and the recent therapeutic advances using copper coordination complexes as anticancer agents.
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    Gandin, V.; Trenti, A.; Porchia, M.; Tisato, F.; Giorgetti, M.; Zanusso, I.; Trevisi, L.; Marzano, C. Homoleptic phosphino copper(i) complexes with in vitro and in vivo dual cytotoxic and anti-angiogenic activity. Metallomics 2015, 7, 1497– 1507,  DOI: 10.1039/C5MT00163C
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    Homoleptic phosphino copper(I) complexes with in vitro and in vivo dual cytotoxic and anti-angiogenic activity
    Gandin, V.; Trenti, A.; Porchia, M.; Tisato, F.; Giorgetti, M.; Zanusso, I.; Trevisi, L.; Marzano, C.
    Metallomics (2015), 7 (11), 1497-1507CODEN: METAJS; ISSN:1756-591X. (Royal Society of Chemistry)
    Homoleptic, tetrahedral Cu(I) complexes of the type [Cu(P)4]BF4 (1-3), where P are the phosphine ligands, 1,3,5-triaza-7-phosphaadamantane (PTA), 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (DAPTA) and 2-thia-1,3,5-triaza-phosphoaadamantane-2,2-dioxide (PTA-SO2), have been prepd. Novel complexes [Cu(DAPTA)4]BF42 and [Cu(PTA-SO2)4]BF43 have been fully characterized by means of spectroscopic methods, corroborated by XAS-EXAFS anal. of 2. In vitro cell culture expts. revealed a significant antiproliferative activity for Cu(I) compds. against several human cancer cell lines derived from solid tumors with preferential cell growth inhibition towards tumor compared to non-malignant cells. In vitro monitoring of migration and capillary-like tube formation of human umbilical vein endothelial cells (HUVECs) showed an anti-angiogenic effect of copper(I) complexes at sub-cytotoxic concns. In vivo studies on the antitumor efficacy and ability to inhibit angiogenesis confirmed the dual cytotoxic and anti-angiogenic properties of Cu(I) derivs.
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    Silva-Platas, C.; Guerrero-Beltrán, C. E.; Carrancá, M.; Castillo, E. C.; Bernal-Ramírez, J.; Oropeza-Almazán, Y.; González, L. N.; Rojo, R.; Martínez, L. E.; Valiente-Banuet, J.; Ruiz-Azuara, L.; Bravo-Gómez, M. E.; García, N.; Carvajal, K.; García-Rivas, G. Antineoplastic copper coordinated complexes (Casiopeinas) uncouple oxidative phosphorylation and induce mitochondrial permeability transition in cardiac mitochondria and cardiomyocytes. J. Bioenerg. Biomembr. 2016, 48, 43– 54,  DOI: 10.1007/s10863-015-9640-x
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    Antineoplastic copper coordinated complexes (Casiopeinas) uncouple oxidative phosphorylation and induce mitochondrial permeability transition in cardiac mitochondria and cardiomyocytes
    Silva-Platas, Christian; Guerrero-Beltran, Carlos Enrique; Carranca, Mariana; Castillo, Elena Cristina; Bernal-Ramirez, Judith; Oropeza-Almazan, Yuriana; Gonzalez, Lorena N.; Rojo, Rocio; Martinez, Luis Enrique; Valiente-Banuet, Juan; Ruiz-Azuara, Lena; Bravo-Gomez, Maria Elena; Garcia, Noemi; Carvajal, Karla; Garcia-Rivas, Gerardo
    Journal of Bioenergetics and Biomembranes (2016), 48 (1), 43-54CODEN: JBBID4; ISSN:0145-479X. (Springer)
    Copper-based drugs, Casiopeinas (Cas), exhibit antiproliferative and antineoplastic activities in vitro and in vivo, resp. Unfortunately, the clin. use of these novel chemotherapeutics could be limited by the development of dose-dependent cardiotoxicity. In addn., the mol. mechanisms underlying Cas cardiotoxicity and anticancer activity are not completely understood. Here, we explore the potential impact of Cas on the cardiac mitochondria energetics as the mol. mechanisms underlying Cas-induced cardiotoxicity. To explore the properties on mitochondrial metab., we detd. Cas effects on respiration, membrane potential, membrane permeability, and redox state in isolated cardiac mitochondria. The effect of Cas on the mitochondrial membrane potential (Δψm) was also evaluated in isolated cardiomyocytes by confocal microscopy and flow cytometry. Cas IIIEa, IIgly, and IIIia predominately inhibited maximal NADH- and succinate-linked mitochondrial respiration, increased the state-4 respiration rate and reduced membrane potential, suggesting that Cas also act as mitochondrial uncouplers. Interestingly, cyclosporine A inhibited Cas-induced mitochondrial depolarization, suggesting the involvement of mitochondrial permeability transition pore (mPTP). Similarly to isolated mitochondria, in isolated cardiomyocytes, Cas treatment decreased the Δψm and cyclosporine A treatment prevented mitochondrial depolarization. The prodn. of H2O2 increased in Cas-treated mitochondria, which might also increase the oxidn. of mitochondrial proteins such as adenine nucleotide translocase. In accordance, an antioxidant scavenger (Tiron) significantly diminished Cas IIIia mitochondrial depolarization. Cas induces a prominent loss of membrane potential, assocd. with alterations in redox state, which increases mPTP opening, potentially due to thiol-dependent modifications of the pore, suggesting that direct or indirect inhibition of mPTP opening might reduce Cas-induced cardiotoxicity.
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    Weekley, C. M.; He, C. Developing drugs targeting transition metal homeostasis. Curr. Opin. Chem. Biol. 2017, 37, 26– 32,  DOI: 10.1016/j.cbpa.2016.12.011
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    Developing drugs targeting transition metal homeostasis
    Weekley, Claire M.; He, Chuan
    Current Opinion in Chemical Biology (2017), 37 (), 26-32CODEN: COCBF4; ISSN:1367-5931. (Elsevier B.V.)
    Metal dyshomeostasis is involved in the pathogenesis and progression of diseases including cancer and neurodegenerative diseases. Metal chelators and ionophores are well known modulators of transition metal homeostasis, and a no. of these mols. are in clin. trials. Metal-binding compds. are not the only drugs capable of targeting transition metal homeostasis. This review presents recent highlights in the development of chelators and ionophores for the treatment of cancer and neurodegenerative disease. Moreover, we discuss the development of small mols. that alter copper and iron homeostasis by inhibiting metal transport proteins. Finally, we consider the emergence of metal regulatory factor 1 as a drug target in diseases where it mediates zinc-induced signalling cascades leading to pathogenesis.
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    Wehbe, M.; Leung, A. W. Y.; Abrams, M. J.; Orvig, C.; Bally, M. B. A Perspective─can copper complexes be developed as a novel class of therapeutics?. Dalton Trans. 2017, 46, 10758– 10773,  DOI: 10.1039/C7DT01955F
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    A Perspective - can copper complexes be developed as a novel class of therapeutics?
    Wehbe, Mohamed; Leung, Ada W. Y.; Abrams, Michael J.; Orvig, Chris; Bally, Marcel B.
    Dalton Transactions (2017), 46 (33), 10758-10773CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
    Although copper-ligand complexes appear to be promising as a new class of therapeutics, other than the family of copper(II) coordination compds. referred to as casiope´inas these compds. have yet to reach the clinic for human use. The pharmaceutical challenges assocd. with developing copper-based therapeutics will be presented in this article along with a discussion of the potential for high-throughput chem., computer-aided drug design, and nanotechnol. to address the development of this important class of drug candidates.
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    Baldari, S.; Di Rocco, G.; Toietta, G. Current Biomedical Use of Copper Chelation Therapy. Int. J. Mol. Sci. 2020, 21, 1069,  DOI: 10.3390/ijms21031069
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    Current biomedical use of copper chelation therapy
    Baldari, Silvia; Rocco, Giuliana Di; Toietta, Gabriele
    International Journal of Molecular Sciences (2020), 21 (3), 1069CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)
    A review. Copper is an essential microelement that plays an important role in a wide variety of biol. processes. Copper concn. has to be finely regulated, as any imbalance in its homeostasis can induce abnormalities. In particular, excess copper plays an important role in the etiopathogenesis of the genetic disease Wilson's syndrome, in neurol. and neurodegenerative pathologies such as Alzheimer's and Parkinson's diseases, in idiopathic pulmonary fibrosis, in diabetes, and in several forms of cancer. Copper chelating agents are among the most promising tools to keep copper concn. at physiol. levels. In this review, we focus on the most relevant compds. exptl. and clin. evaluated for their ability to counteract copper homeostasis deregulation. In particular, we provide a general overview of the main disorders characterized by a pathol. increase in copper levels, summarizing the principal copper chelating therapies adopted in clin. trials.
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    Santini, C.; Pellei, M.; Gandin, V.; Porchia, M.; Tisato, F.; Marzano, C. Advances in Copper Complexes as Anticancer Agents. Chem. Rev. 2014, 114, 815– 862,  DOI: 10.1021/Cr400135x
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    Advances in Copper Complexes as Anticancer Agents
    Santini, Carlo; Pellei, Maura; Gandin, Valentina; Porchia, Marina; Tisato, Francesco; Marzano, Cristina
    Chemical Reviews (Washington, DC, United States) (2014), 114 (1), 815-862CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    This review describes advances in the synthesis, design, and development of copper complexes as anticancer agents in the last 4 years. Interest in this field has rapidly grown in recent years, as illustrated by the increasing no. of publications reported since 2000. This summary covers the period 2008-2012 and follows the authors' previous efforts in the same area. Furthermore, the authors summarize recent findings on (i) identification of the main mol. targets and cellular pathways involved in the copper complexes-induced antiproliferative effects and (ii) the state of art of in vivo studies on the antitumor activity of copper compds. This overview would like to be a useful tool for the research community actively involved in the copper-based anticancer drug discovery.
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    Lelièvre, P.; Sancey, L.; Coll, J.-L.; Deniaud, A.; Busser, B. The Multifaceted Roles of Copper in Cancer: A Trace Metal Element with Dysregulated Metabolism, but Also a Target or a Bullet for Therapy. Cancers 2020, 12, 3594,  DOI: 10.3390/cancers12123594
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    The multifaceted roles of copper in cancer: a trace metal element with dysregulated metabolism, but also a target or a bullet for therapy
    Lelievre, Pierre; Sancey, Lucie; Coll, Jean-Luc; Deniaud, Aurelien; Busser, Benoit
    Cancers (2020), 12 (12), 3594CODEN: CANCCT; ISSN:2072-6694. (MDPI AG)
    In the human body, copper (Cu) is a major and essential player in a large no. of cellular mechanisms and signaling pathways. The involvement of Cu in oxidn.-redn. reactions requires close regulation of copper metab. in order to avoid toxic effects. In many types of cancer, variations in copper protein levels have been demonstrated. These variations result in increased concns. of intratumoral Cu and alterations in the systemic distribution of copper. Such alterations in Cu homeostasis may promote tumor growth or invasiveness or may even confer resistance to treatments. Once characterized, the dysregulated Cu metab. is pinpointing several promising biomarkers for clin. use with prognostic or predictive capabilities. The altered Cu metab. in cancer cells and the different responses of tumor cells to Cu are strongly supporting the development of treatments to disrupt, deplete, or increase Cu levels in tumors. The metallic nature of Cu as a chem. element is key for the development of anticancer agents via the synthesis of nanoparticles or copper-based complexes with antineoplastic properties for therapy. Finally, some of these new therapeutic strategies such as chelators or ionophores have shown promising results in a preclin. setting, and others are already in the clinic.
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    Medici, S.; Peana, M.; Nurchi, V. M.; Lachowicz, J. I.; Crisponi, G.; Zoroddu, M. A. Noble metals in medicine: Latest advances. Coord. Chem. Rev. 2015, 284, 329– 350,  DOI: 10.1016/j.ccr.2014.08.002
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    Noble metals in medicine: Latest advances
    Medici, Serenella; Peana, Massimiliano; Nurchi, Valeria Marina; Lachowicz, Joanna I.; Crisponi, Guido; Zoroddu, Maria Antonietta
    Coordination Chemistry Reviews (2015), 284 (), 329-350CODEN: CCHRAM; ISSN:0010-8545. (Elsevier B.V.)
    A review. History shows that metal-based drugs and remedies have been known and used since very ancient times. For example, silver was employed in the treatment of wounds and ulcers according to the Greek physician Hippocrates, but its antimicrobial properties had probably been recognized long before because it was used to make vessels for storing liqs. in pure form. The ancient Egyptians also knew how to sterilize water with copper. The medical use of gold can be dated back to 2500 B.C. in China. However, the new era of metal-based medicine started almost 50 years ago when cisplatin was shown to inhibit cellular division in Escherichia coli, thereby leading to the first studies of its antitumor activity in rats and its assessment as one of the most powerful drugs for use against different types of cancer, although many other novel metal-based drugs are promising and they are attracting growing attention in modern clin. medicine. Gold salts and arsenic compds. have been in use for decades in the treatment of rheumatoid arthritis and syphilis, resp., but studies of cisplatin have definitely shifted the attention of researchers to the pool of transition "heavy" metals as potential therapeutic agents. Rhodium, iridium, palladium, osmium, and the other so-called noble elements have been the subjects of intensive investigations, thereby leading to the prodn. of a series of complex compds. with remarkable anticancer activities, as well as antirheumatic, antimalarial, and antimicrobial drugs. The no. of published studies in this field is huge and they have already been the subjects of careful review. In this review, we provide a detailed account of the latest results (2010-2013) and their potential uses in the cure of severe diseases.
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    Tisato, F.; Marzano, C.; Porchia, M.; Pellei, M.; Santini, C. Copper in Diseases and Treatments, and Copper-Based Anticancer Strategies. Med. Res. Rev. 2010, 30, 708– 749,  DOI: 10.1002/Med.20174
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    Copper in diseases and treatments, and copper-based anticancer strategies
    Tisato, Francesco; Marzano, Cristina; Porchia, Marina; Pellei, Maura; Santini, Carlo
    Medicinal Research Reviews (2010), 30 (4), 708-749CODEN: MRREDD; ISSN:0198-6325. (John Wiley & Sons, Inc.)
    A review. Copper is found in all living organisms and is a crucial trace element in redox chem., growth and development. It is important for the function of several enzymes and proteins involved in energy metab., respiration, and DNA synthesis, notably cytochrome oxidase, superoxide dismutase, ascorbate oxidase, and tyrosinase. The major functions of copper-biol. mols. involve oxidn.-redn. reactions in which they react directly with mol. oxygen to produce free radicals. Therefore, copper requires tightly regulated homeostatic mechanisms to ensure adequate supplies without any toxic effects. Overload or deficiency of copper is assocd., resp., with Wilson disease (WD) and Menkes disease (MD), which are of genetic origin. Researches on Menkes and Wilson disorders have provided useful insights in the field of copper homeostasis and in particular into the understanding of intracellular trafficking and distribution of copper at mol. levels. Therapies based on metal supplementation with copper histidine or removal of copper excess by means of specific copper chelators are currently effective in treating MD and WD, resp. Copper chelation therapy is now attracting much attention for the investigation and treatment of various neurodegenerative disorders such as Alzheimer, Parkinson and CreutzfeldtJakob. An excess of copper appears to be an essential co-factor for angiogenesis. Moreover, elevated levels of copper have been found in many types of human cancers, including prostate, breast, colon, lung, and brain. On these basis, the employment of copper chelators has been reported to be of therapeutic value in the treatment of several types of cancers as anti-angiogenic mols. More recently, mixts. of copper chelators with copper salts have been found to act as efficient proteasome inhibitors and apoptosis inducers, specifically in cancer cells. Moreover, following the worldwide success of platinum(II) compds. in cancer chemotherapy, several families of individual copper complexes have been studied as potential antitumor agents. These investigations, revealing the occurrence of mechanisms of action quite different from platinum drugs, head toward the development of new anticancer metallodrugs with improved specificity and decreased toxic side effects.
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    Marzano, C.; Pellei, M.; Tisato, F.; Santini, C. Copper complexes as anticancer agents. Anti-Cancer Agents Med. Chem. 2009, 9, 185– 211,  DOI: 10.2174/187152009787313837
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    Copper complexes as anticancer agents
    Marzano, Cristina; Pellei, Maura; Tisato, Francesco; Santini, Carlo
    Anti-Cancer Agents in Medicinal Chemistry (2009), 9 (2), 185-211CODEN: AAMCE4; ISSN:1871-5206. (Bentham Science Publishers Ltd.)
    A review. Metal-based antitumor drugs play a relevant role in antiblastic chemotherapy. Cisplatin is regarded as one of the most effective drugs, even if severe toxicities and drug resistance phenomena limit its clin. use. Therefore, in recent years there has been a rapid expansion in research and development of novel metal-based anticancer drugs to improve clin. effectiveness, to reduce general toxicity and to broaden the spectrum of activity. The variety of metal ion functions in biol. has stimulated the development of new metallo drugs other than Pt drugs with the aim to obtain compds. acting via alternative mechanisms of action. Among non-Pt compds., copper complexes are potentially attractive as anticancer agents. Actually, since many years a lot of researches have actively investigated copper compds. based on the assumption proposal that endogenous metals may be less toxic. It has been established that the properties of copper-coordinated compds. are largely detd. by the nature of ligands and donor atoms bound to the metal ion. In this review, the most remarkable achievements in the design and development of copper(I, II) complexes as antitumor agents are discussed. Special emphasis has been focused on the identification of structure-activity relationships for the different classes of copper(I,II) complexes. This work was motivated by the observation that no comprehensive surveys of copper complexes as anticancer agents were available in the literature. Moreover, up to now, despite the enormous efforts in synthesizing different classes of copper complexes, very few data concerning the mol. basis of the mechanisms underlying their antitumor activity are available. This overview, collecting the most significant strategies adopted in the last ten years to design promising anticancer copper(I,II) compds., would be a help to the researchers working in this field.
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    Zehra, S.; Tabassum, S.; Arjmand, F. Biochemical pathways of copper complexes: progress over the past 5 years. Drug Discovery Today 2021, 26, 1086– 1096,  DOI: 10.1016/j.drudis.2021.01.015
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    Biochemical pathways of copper complexes: progress over the past 5 years
    Zehra, Siffeen; Tabassum, Sartaj; Arjmand, Farukh
    Drug Discovery Today (2021), 26 (4), 1086-1096CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)
    A review. Copper is an essential trace element with vital roles in many metalloenzymes; it is also prominent among nonplatinum anticancer metallodrugs. Copper-based complexes are endogenously biocompatible, tenfold more potent than cisplatin, exhibit fewer adverse effects, and have a wide therapeutic window. In cancer biol., copper acts as an antitumor agent by inhibiting cancer via multiple pathways. Herein, we present an overview of advances in copper complexes as 'lead' antitumor drug candidates, and in understanding their biochem. and pharmacol. pathways over the past 5 years. This review will help to develop more efficacious therapeutics to improve clin. outcomes for cancer treatments.
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    Singh, N. K.; Kumbhar, A. A.; Pokharel, Y. R.; Yadav, P. N. Anticancer potency of copper(II) complexes of thiosemicarbazones. J. Inorg. Biochem. 2020, 210, 111134,  DOI: 10.1016/j.jinorgbio.2020.111134
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    Anticancer potency of copper(II) complexes of thiosemicarbazones
    Singh, Narendra Kumar; Kumbhar, Anupa A.; Pokharel, Yuba Raj; Yadav, Paras Nath
    Journal of Inorganic Biochemistry (2020), 210 (), 111134CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier Inc.)
    A review. Being a structural and catalytic cofactor in a no. of biol. pathways, copper accumulates in tumors owing to selective permeability of the cancer cell membranes. Copper(II) ion forms the active centers in a large no. of metalloproteins. The coordination of Schiff's base ligands to the metal ion results in the high extent of increase in anticancer activity. The copper(II) complexes can cleave DNA through oxidative and hydrolytic pathways, cell apoptosis via intrinsic reactive oxygen species (ROS) mediated mitochondrial pathway due to excessive prodn. of ROS and hence, are found more active than Ni and Pt complexes. Flexible Cu(I/II) redox behavior helps the copper complexes to form more potent, clin. effective and less toxic copper based antiproliferative drugs of lower IC50 value and higher growth inhibitory activity. Copper(II) complexes of thiosemicarbazones of Isatin, Pyridine, Benzoyl pyridine, Diacetyl/Dimethyl glyoxal, Acetophenone/Acetoacetanalide, Thiazole/Pyrazole, Quinoline, Carboxybenzaldehyde, Cinnamaldehyde/Cuminaldehyde, Citronellal, Chromone, Pyridoxal, 8-Ethyl-2-hydroxytricyclo (7.3.1.02,7) tridecan-13-one, Acyl Diazines, Naphthalene, Proline, 5-Formyluracil, 2-Hydroxy-8-propyltricyclo (7.3.1.02,7) tridecan-13-one, 9-cis-Retinal, Curcumin, Helicin (Salicylaldehyde-β-D-glucoside), Thiophene carboxaldehyde, Salicylaldehyde, Iminodiacetate, and 3-Formyl-4-hydroxy benzenesulfonic acid have been found to exhibit more anticancer activity toward HCT116, MCF7, A549, U937, HeLa, HepG2, SGC-7901, A2780 cell lines than that of their corresponding thiosemicarbazones and std. topoisomerase-II inhibitors.
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    Allardyce, C. S.; Dyson, P. J. Metal-based drugs that break the rules. Dalton Trans. 2016, 45, 3201– 3209,  DOI: 10.1039/C5DT03919C
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    Metal-based drugs that break the rules
    Allardyce, Claire S.; Dyson, Paul J.
    Dalton Transactions (2016), 45 (8), 3201-3209CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
    Cisplatin and other platinum compds. have had a huge impact in the treatment of cancers and are applied in the majority of anticancer chemotherapeutic regimens. The success of these compds. has biased the approaches used to discover new metal-based anticancer drugs. In this perspective we highlight compds. that are apparently incompatible with the more classical (platinum-derived) concepts employed in the development of metal-based anticancer drugs, with respect to both compd. design and the approaches used to validate their utility. Possible design approaches for the future are also suggested.
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    Spreckelmeyer, S.; Orvig, C.; Casini, A. Cellular Transport Mechanisms of Cytotoxic Metallodrugs: An Overview beyond Cisplatin. Molecules 2014, 19, 15584– 15610,  DOI: 10.3390/molecules191015584
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    Cellular transport mechanisms of cytotoxic metallodrugs: an overview beyond cisplatin
    Spreckelmeyer, Sarah; Orvig, Chris; Casini, Angela
    Molecules (2014), 19 (10), 15584-15610, 27 pp.CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
    A review. The field of medicinal inorg. chem. has grown consistently during the past 50 years; however, metal-contg. coordination compds. represent only a minor proportion of drugs currently on the market, indicating that research in this area has not yet been thoroughly realized. Although platinum-based drugs as cancer chemotherapeutic agents have been widely studied, exact knowledge of the mechanisms governing their accumulation in cells is still lacking. However, evidence suggests active uptake and efflux mechanisms are involved; this may be involved also in other exptl. metal coordination and organometallic compds. with promising antitumor activities in vitro and in vivo, such as ruthenium and gold compds. Such knowledge would be necessary to elucidate the balance between activity and toxicity profiles of metal compds. In this review, we present an overview of the information available on the cellular accumulation of Pt compds. from in vitro, in vivo and clin. studies, as well as a summary of reports on the possible accumulation mechanisms for different families of exptl. anticancer metal complexes (e.g., Ru Au and Ir). Finally, we discuss the need for rationalization of the investigational approaches available to study metallodrug cellular transport.
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    Zaki, M.; Arjmand, F.; Tabassum, S. Current and future potential of metallo drugs: Revisiting DNA-binding of metal containing molecules and their diverse mechanism of action. Inorg. Chim. Acta 2016, 444, 1– 22,  DOI: 10.1016/j.ica.2016.01.006
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    Current and future potential of metallo drugs: Revisiting DNA-binding of metal containing molecules and their diverse mechanism of action
    Zaki, Mehvash; Arjmand, Farukh; Tabassum, Sartaj
    Inorganica Chimica Acta (2016), 444 (), 1-22CODEN: ICHAA3; ISSN:0020-1693. (Elsevier B.V.)
    A review. Cancer treatments regimes which include conventional chemotherapy have not proved so successful in curing human malignancies. Failures to these treatment modalities include inherent resistance, systemic toxicity and severe side effects. Out of 50% patients administrated to chemotherapy, only 5% undergoes survival. Therefore, identification of new drug design and therapeutic strategies that could target cancer cells leaving normal cells unaffected still continues to be a challenge. Despite advances that have led to the development of new therapies, treatment options are still limited for many types of human cancers particularly with those undifferentiated phenotypes. This review provides an overview of metal based anticancer drugs in clin. trials and the serious side effects caused by these drugs led the chemists to search for the new diagnostic and therapeutic agents. In particular, the authors focus on metal complexes of copper, zinc, silver and gold complexes with an emphasis on the new strategies used in the development of new antitumor agents.
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    Molinaro, C.; Martoriati, A.; Pelinski, L.; Cailliau, K. Copper Complexes as Anticancer Agents Targeting Topoisomerases I and II. Cancers 2020, 12, 2863,  DOI: 10.3390/cancers12102863
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    Copper complexes as anticancer agents targeting topoisomerases I and II
    Molinaro, Caroline; Martoriati, Alain; Pelinski, Lydie; Cailliau, Katia
    Cancers (2020), 12 (10), 2863CODEN: CANCCT; ISSN:2072-6694. (MDPI AG)
    Organometallics, such as copper compds., are cancer chemotherapeutics used alone or in combination with other drugs. One small group of copper complexes exerts an effective inhibitory action on topoisomerases, which participate in the regulation of DNA topol. Copper complexes inhibitors of topoisomerases 1 and 2 work by different mol. mechanisms, analyzed herein. They allow genesis of DNA breaks after the formation of a ternary complex, or act in a catalytic mode, often display DNA intercalative properties and ROS prodn., and sometimes display dual effects. These amplified actions have repercussions on the cell cycle checkpoints and death effectors. Copper complexes of topoisomerase inhibitors are analyzed in a broader synthetic view and in the context of cancer cell mutations. Finally, new emerging treatment aspects are depicted to encourage the expansion of this family of highly active anticancer drugs and to expend their use in clin. trials and future cancer therapy.
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    Zanella, A.; Gandin, V.; Porchia, M.; Refosco, F.; Tisato, F.; Sorrentino, F.; Scutari, G.; Rigobello, M. P.; Marzano, C. Cytotoxicity in human cancer cells and mitochondrial dysfunction induced by a series of new copper(I) complexes containing tris(2-cyanoethyl)phosphines. Invest. New Drugs 2011, 29, 1213– 1223,  DOI: 10.1007/s10637-010-9466-7
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    Cytotoxicity in human cancer cells and mitochondrial dysfunction induced by a series of new copper(I) complexes containing tris(2-cyanoethyl)phosphines
    Zanella, Alessandro; Gandin, Valentina; Porchia, Marina; Refosco, Fiorenzo; Tisato, Francesco; Sorrentino, Francesca; Scutari, Guido; Rigobello, Maria Pia; Marzano, Cristina
    Investigational New Drugs (2011), 29 (6), 1213-1223CODEN: INNDDK; ISSN:0167-6997. (Springer)
    Over the last few years a lot of research has been done to develop novel metal-based anti-cancer drugs, with the aim of improving clin. effectiveness, reducing general toxicity, and broadening the spectrum of activity. The search for novel metal-based antitumor drugs other than Pt agents includes the investigation of the cytotoxic activity of copper(I/II) compds. Among these copper agents, particular attention has been recently devoted to hydrophilic copper(I) species bearing phosphines because of their noteworthy stability in aq. media together with their remarkable in vitro cytotoxic activity. In this study we report on the synthesis, characterization and cytotoxic assays of a series of Cu(I) complexes with tris(2-cyanoethyl)phosphine (PCN) and bis(2-cyanoethyl)phenylphosphine (PCNPh). They were prepd. by reaction of [Cu(CH3CN)4]+ or CuX2 precursors with the pertinent phosphine in acetone or acetonitrile solns. producing compds. of the following formulation: [Cu(PCN)2]+ 2, [Cu(CH3CN)(PCN)]+ 3, [Cu(X)(PCN)] (X = Cl, 4; Br, 5), and [Cu(PCNPh)2]+ 6. The new copper(I) complexes were tested for their cytotoxic properties against a panel of several human tumor cell lines. Cellular copper uptake rate was correlated with cell growth inhibition in 2008 human ovarian cancer cells. Moreover, copper(I)-PCN complexes were evaluated for their ability to alter the most relevant mitochondrial pathophysiol. parameters such as respiration, coupling, ATP-synthetase activity and membrane potential in isolated mitochondria. These data were correlated with changes in mitochondrial membrane potential and prodn. of reactive oxygen species (ROS) in drug-treated 2008 cells.
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  48. 48
    Otero, A.; Fernández-Baeza, J.; Lara-Sánchez, A.; Sánchez-Barba, L. F. Metal complexes with heteroscorpionate ligands based on the bis(pyrazol-1-yl)methane moiety: Catalytic chemistry. Coord. Chem. Rev. 2013, 257, 1806– 1868,  DOI: 10.1016/j.ccr.2013.01.027
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    Metal complexes with heteroscorpionate ligands based on the bis(pyrazol-1-yl)methane moiety: Catalytic chemistry
    Otero, Antonio; Fernandez-Baeza, Juan; Lara-Sanchez, Agustin; Sanchez-Barba, Luis F.
    Coordination Chemistry Reviews (2013), 257 (11-12), 1806-1868CODEN: CCHRAM; ISSN:0010-8545. (Elsevier B.V.)
    A review. This review covers studies related to the design of ligands, synthetic pathways and catalytic processes of some families of metal complexes that contain heteroscorpionate ligands based on bis(pyrazol-1-yl)methane moieties.
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  49. 49
    Pellei, M.; Papini, G.; Trasatti, A.; Giorgetti, M.; Tonelli, D.; Minicucci, M.; Marzano, C.; Gandin, V.; Aquilanti, G.; Dolmella, A.; Santini, C. Nitroimidazole and glucosamine conjugated heteroscorpionate ligands and related copper(II) complexes. Syntheses, biological activity and XAS studies. Dalton Trans. 2011, 40, 9877– 9888,  DOI: 10.1039/c1dt10486a
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    49
    Nitroimidazole and glucosamine conjugated heteroscorpionate ligands and related copper(II) complexes. Syntheses, biological activity and XAS studies
    Pellei, Maura; Papini, Grazia; Trasatti, Andrea; Giorgetti, Marco; Tonelli, Domenica; Minicucci, Marco; Marzano, Cristina; Gandin, Valentina; Aquilanti, Giuliana; Dolmella, Alessandro; Santini, Carlo
    Dalton Transactions (2011), 40 (38), 9877-9888CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
    New nitroimidazole and glucosamine conjugated heteroscorpionate ligands, 2,2-bis(3,5-dimethyl-1H-pyrazol-1-yl)-N-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)acetamide (LMN) and 1,3,4,6-tetra-O-acetyl-2-{[bis(3,5-dimethyl-1H-pyrazol-1-yl)acetyl]amino}-2-deoxy-β-d-glucopyranose (LDAC), resp., were synthesized by direct coupling of preformed side chain acid and amine components. The related Cu(II) complexes {[(LMN)2Cu]Cl2}, and {[(LDAC)2Cu]Cl2} were prepd. from the reaction of CuCl2.2H2O with LMN or LDAC ligand in MeOH soln. Single crystal structural characterization was undertaken for the LMN ligand. In the absence of a coordinated metal core, the overall arrangement of the ligand was detd. by some loose intra- and inter-mol. nonbonding contacts. X-ray Absorption Spectroscopy (XAS) was used to probe the local structure of the two Cu(II) complexes, {[(LMN)2Cu]Cl2} and {[(LDAC)2Cu]Cl2}. The EXAFS anal. has permitted the identification of the local environment of the Cu site. Cu interacts with 2 units of ligand in both complexes, and it is 6-fold coordinated. Its local structure is described by four Cu-N and two Cu-O interactions to form a pseudo-octahedron core, with a 0.14 Å lengthening of the Cu-O bond length in the case of LDAC complex with respect to the LMN one, likely due to the higher steric hindrance of the glucosamine moiety. The XANES anal. agrees with these results, also confirming the Cu(II) formal Cu oxidn. state for both complexes. The new Cu(II) complexes {[(LMN)2Cu]Cl2} and {[(LDAC)2Cu]Cl2} as well as the corresponding uncoordinated ligands were evaluated for their cytotoxic activity towards a panel of several human tumor cell lines. Both Cu(II) complexes show similar spectra of cytotoxicity and very low resistance factors (RF < 2) against C13* ovarian cancer cells which have acquired resistance to cisplatin.
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    Giorgetti, M.; Tonelli, S.; Zanelli, A.; Aquilanti, G.; Pellei, M.; Santini, C. Synchrotron radiation X-ray absorption spectroscopic studies in solution and electrochemistry of a nitroimidazole conjugated heteroscorpionate copper(II) complex. Polyhedron 2012, 48, 174– 180,  DOI: 10.1016/j.poly.2012.08.073
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    50
    Synchrotron radiation X-ray absorption spectroscopic studies in solution and electrochemistry of a nitroimidazole conjugated heteroscorpionate copper(II) complex
    Giorgetti, Marco; Tonelli, Silvia; Zanelli, Alberto; Aquilanti, Giuliana; Pellei, Maura; Santini, Carlo
    Polyhedron (2012), 48 (1), 174-180CODEN: PLYHDE; ISSN:0277-5387. (Elsevier Ltd.)
    Synchrotron radiation x-ray absorption spectroscopy was used to det. the soln. structure of the nitroimidazole conjugated heteroscorpionate Cu(II) complex {[(LMN)2Cu]Cl2} (LMN = 2,2-bis(3,5-dimethyl-1H-pyrazol-1-yl)-N-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)acetamide) at three different pH values. The strategy used for the XAS data anal. for a straightforward data interpretation is presented. The Cu center is coordinated by two mols. of ligands, describing a quasi-octahedral figure, in all studied solns., demonstrating the stability of the complex in soln. The Cu complex displays a pH dependence where the Cu-O first shell distance (from the carbonyl) lengthens at acid pH; the Cu-N equatorial distances are almost the same. XANES spectroscopy also indicates structural rearrangements occurring in soln. at various pH, where the spectrum at pH 4.4 displays the largest differences from the other ones. The cyclic voltammetry curves obtained on the same solns. show an irreversible peak due to the redn. of Cu(II) → Cu(I), which falls at potential of ∼0.4-0.5 V vs. SCE, and it is depending on pH. The potentiality of the joint XAS and electrochem. approach in the detn. of the structural characteristics of the solns. is highlighted.
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  51. 51
    Morelli, M. B.; Amantini, C.; Santoni, G.; Pellei, M.; Santini, C.; Cimarelli, C.; Marcantoni, E.; Petrini, M.; Del Bello, F.; Giorgioni, G.; Piergentili, A.; Quaglia, W. Novel antitumor copper(ii) complexes designed to act through synergistic mechanisms of action, due to the presence of an NMDA receptor ligand and copper in the same chemical entity. New J. Chem. 2018, 42, 11878– 11887,  DOI: 10.1039/c8nj01763h
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    51
    Novel antitumor copper(II) complexes designed to act through synergistic mechanisms of action, due to the presence of an NMDA receptor ligand and copper in the same chemical entity
    Morelli, Maria Beatrice; Amantini, Consuelo; Santoni, Giorgio; Pellei, Maura; Santini, Carlo; Cimarelli, Cristina; Marcantoni, Enrico; Petrini, Marino; Del Bello, Fabio; Giorgioni, Gianfabio; Piergentili, Alessandro; Quaglia, Wilma
    New Journal of Chemistry (2018), 42 (14), 11878-11887CODEN: NJCHE5; ISSN:1144-0546. (Royal Society of Chemistry)
    In the present article the 1,4-dioxane deriv. 1, a potent noncompetitive NMDA receptor antagonist, showed cytotoxic activity in the MCF7 breast cancer cell line significantly higher than those of the functionally related compds. (S)-(+)-ketamine and MK-801. Encouraged by this result and considering that copper complexes have been highlighted to be promising anticancer agents, the NMDA receptor ligand 1 was linked to the bifunctionalizable species 2 and 3, affording the conjugated derivs. 4 and 5 that were used for the prepn. of the stable Cu(II) complexes 6 and 7. All the compds. were evaluated against a panel of human cancer cell lines derived from solid tumors. Complex 7 showed the best antitumor activity in all the studied cell lines. This result suggests that 7 might act through synergistic mechanisms of action due to the presence of the NMDA ligand 1 and copper(II) in the same chem. entity. Furthermore, the cellular mechanisms affected by complex 7 were assessed through cytofluorimetric and western blot analyses. Data suggested the induction of cell death through paraptosis mediated by endoplasmic reticulum (ER) stress.
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  52. 52
    Pellei, M.; Bagnarelli, L.; Luciani, L.; Del Bello, F.; Giorgioni, G.; Piergentili, A.; Quaglia, W.; De Franco, M.; Gandin, V.; Marzano, C.; Santini, C. Synthesis and Cytotoxic Activity Evaluation of New Cu(I) Complexes of Bis(pyrazol-1-yl) Acetate Ligands Functionalized with an NMDA Receptor Antagonist. Int. J. Mol. Sci. 2020, 21, 2616,  DOI: 10.3390/ijms21072616
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    Synthesis and cytotoxic activity evaluation of new Cu(I) complexes of bis(pyrazol-1-yl) acetate ligands functionalized with an NMDA receptor antagonist
    Pellei, Maura; Bagnarelli, Luca; Luciani, Lorenzo; Del Bello, Fabio; Giorgioni, Gianfabio; Piergentili, Alessandro; Quaglia, Wilma; De Franco, Michele; Gandin, Valentina; Marzano, Cristina; Santini, Carlo
    International Journal of Molecular Sciences (2020), 21 (7), 2616CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)
    In the present article, copper(I) complexes of bis(pyrazol-1-yl) carboxylic acid (LH), bis(3,5-dimethylpyrazol-1-yl) carboxylic acid (L2H), and bis(pyrazol-1-yl) acetates conjugated with an N-methyl-D-aspartate (NMDA) receptor antagonist (LNMDA or L2NMDA) and phosphane ligands (triphenylphosphine or 1,3,5-triaza-7-phosphaadamantane) were synthesized. The selection of an NMDA antagonist for the coupling with LH and L2H was suggested by the observation that NMDA receptors are expressed and play a role in different types of cancer models. All the new complexes showed a significant antitumor activity on a panel of human tumor cell lines of different histol., with cisplatin-sensitive, cisplatin-resistant, or multi-drug-resistant phenotype. Their half maximal inhibitory concn. (IC50) values were in the low- and sub-micromolar range and, in general, significantly lower than that of cisplatin. Interestingly, the fact that all the complexes proved to be significantly more active than cisplatin even in three-dimensional (3D) spheroids of H157 and BxPC3 cancer cells increased the relevance of the in vitro results. Finally, morphol. anal. revealed that the most representative complex 8 induced a massive swelling of the endoplasmic reticulum (ER) membrane, which is a clear sign of ER stress.
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    Schiesaro, I.; Venditti, I.; Pellei, M.; Santini, C.; Bagnarelli, L.; Iucci, G.; Battocchio, C.; Meneghini, C. Metal Coordination Core in Copper(II) Complexes Investigated by XAFS. Synchrotron Radiation Science and Applications; Springer Proceedings in Physics; Springer, 2021; Vol. 2021; pp 169– 179.
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    Beck, A.; Weibert, B.; Burzlaff, N. MonoanionicN,N,O-Scorpionate Ligands and their Iron(II) and Zinc(II) Complexes: Models for Mononuclear Active Sites of Non-Heme Iron Oxidases and Zinc Enzymes. Eur. J. Inorg. Chem. 2001, 2001, 521– 527,  DOI: 10.1002/1099-0682(200102)2001:2<521::aid-ejic521>3.0.co;2-q
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    Burzlaff, N.; Hegelmann, I.; Weibert, B. Bis(pyrazol-1-yl)acetates as tripodal “scorpionate” ligands in transition metal carbonyl chemistry: syntheses, structures and reactivity of manganese and rhenium carbonyl complexes of the type [LM(CO)3] (L = bpza, bdmpza). J. Organomet. Chem. 2001, 626, 16– 23,  DOI: 10.1016/s0022-328x(01)00648-9
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    Bis(pyrazol-1-yl)acetates as tripodal "scorpionate" ligands in transition metal carbonyl chemistry: syntheses, structures and reactivity of manganese and rhenium carbonyl complexes of the type [LM(CO)3] (L = bpza, bdmpza)
    Burzlaff, N.; Hegelmann, I.; Weibert, B.
    Journal of Organometallic Chemistry (2001), 626 (1-2), 16-23CODEN: JORCAI; ISSN:0022-328X. (Elsevier Science S.A.)
    The coordination of the ligands bis(3,5-dimethylpyrazol-1-yl)acetate (bdmpza) and bis(pyrazol-1-yl)acetate (bpza) to Group VII metal carbonyls was studied. [LM(CO)3], where M = Mn, Re and L = bpza, bdmpza (2a-3b), were synthesized. [(Bdmpza)Mn(CO)3] (2b), [(bpza)Re(CO)3] (3a) and [(bdmpza)Re(CO)3] (3b), and bis(pyrazol-1-yl)acetic acid (1a) were characterized by single-crystal x-ray analyses. Based on IR-spectroscopic and structural data the electronic properties of these ligands are compared with those of Tp, TpMe2, Cp and Cp*. The reaction of [(bdmpza)Re(CO)3] (3b) with NOBF4 afforded [(bdmpza)Re(CO)2(NO)]BF4 (4).
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    Clark, D. T.; Lilley, D. M. J. Molecular core binding energies for some five membered ring heterocycles as determined by X-ray photoelectron spectroscopy. Chem. Phys. Lett. 1971, 9, 234– 237,  DOI: 10.1016/0009-2614(71)85038-8
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    Molecular core binding energies for some five-membered ring heterocycles as determined by x-ray photoelectron spectroscopy
    Clark, David Thomas; Lilley, D. M. J.
    Chemical Physics Letters (1971), 9 (3), 234-7CODEN: CHPLBC; ISSN:0009-2614.
    The binding energies, detd. by x-ray photoelectron spectroscopy, for the C, S, N, and O atoms in thiophene, pyrrole, furan, isoxazole, pyrazole, imidazole, and thiazole reflect the variations in the electronegativities of the heteroatoms. The exptl. mol. core binding energies are correlated with the variations in the orbital energies and with the variations in the at. charge distributions, which were obtained from nonempirical and semiempirical LCAO MO calcns.
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    Polzonetti, G.; Battocchio, C.; Goldoni, A.; Larciprete, R.; Carravetta, V.; Paolesse, R.; Russo, M. V. Interface formation between C60 and diethynyl-Zn-porphyrinato investigated by SR-induced photoelectron and near-edge X-ray absorption (NEXAFS) spectroscopies. Chem. Phys. 2004, 297, 307– 314,  DOI: 10.1016/j.chemphys.2003.10.024
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    Interface formation between C60 and diethynyl-Zn-porphyrinato investigated by SR-induced photoelectron and near-edge X-ray absorption (NEXAFS) spectroscopies
    Polzonetti, G.; Battocchio, C.; Goldoni, A.; Larciprete, R.; Carravetta, V.; Paolesse, R.; Russo, M. V.
    Chemical Physics (2004), 297 (1-3), 307-314CODEN: CMPHC2; ISSN:0301-0104. (Elsevier Science B.V.)
    C60 doping of multilayer 2,8,12,18-tetraethyl-5,15-diethynyl-3,7,13,17-tetramethylporphyrinato-Zn(II) (Zn-Pf) has been accomplished. The sublimed Zn-Pf mols. initially lay flat on the Cu(1 1 1) substrate and progressively tilt their arrangement in order to be oriented with the mol. plane nearly perpendicular to the Cu(1 1 1) substrate surface, at both monolayer and multilayer coverage, as detected by NEXAFS spectroscopy at the N K-edge. It is noteworthy that C60 interacts with the Zn-Pf sample film producing a perturbation of the electronic structure reflected in the spectral changes at the C1s core level, at the N1s and shake-up satellites of Zn-Pf and in the VB region. By the strong spectral modification that occurs at the Zn-Pf multilayer sample C60 diffusion into the substrate is also argued, giving rise most probably to an intercalated composite assembly with C60 spheres in between two Zn-Pf planes. The obsd. changes are interpreted in terms of charge transfer taking place from C60 to Zn-Pf with a lowering of the band gap and presence of occupied states closer to EF.
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    Battocchio, C.; Fratoddi, I.; Iucci, G.; Russo, M. V.; Goldoni, A.; Parent, P.; Polzonetti, G. Dinuclear Pt and Pd complexes with metalloporphyrin bridges: A NEXAFS study of the electronic structure and self-assembling properties. Mater. Sci. Eng., C 2007, 27, 1338– 1342,  DOI: 10.1016/j.msec.2006.06.014
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    Dinuclear Pt and Pd complexes with metalloporphyrin bridges: A NEXAFS study of the electronic structure and self-assembling properties
    Battocchio, C.; Fratoddi, I.; Iucci, G.; Russo, M. V.; Goldoni, A.; Parent, Ph.; Polzonetti, G.
    Materials Science & Engineering, C: Biomimetic and Supramolecular Systems (2007), 27 (5-8), 1338-1342CODEN: MSCEEE; ISSN:0928-4931. (Elsevier B.V.)
    Binuclear Zn-porphinate-bridged platinum and palladium acetylides were prepd. and studied by K-edge NEXAFS spectroscopy. The complexes, cis,cis-[(PBu3)2ClPtC≡CXC≡CPtCl(PBu3)2] (Pt-ZnDEP) and trans,trans-[(PBu3)2(R)PdC≡CXC≡CPd(R)(PBu3)2] [Pt-ZnDEP, Pd-ZnDEP, resp., X = Zn(2+)-2,8,12,18-tetraethyl-3,7,13,17-tetramethylporphinate(2-)-5,15-diyl; R = PhC≡C] were prepd. by coupling of the diyne HC≡CXC≡CH (ZnDEP) and [(PBu3)2PtCl2] and [(PBu3)2(R)PdCl], resp. The complexes Pt-ZnDEP and Pd-ZnDEP were investigated by means of Near Edge X-ray Absorption Fine Structure spectroscopy (NEXAFS). N K-edge spectra collected on the two macromol. arrays were compared with data on ZnDEP and 2,8,12,18-tetraethyl-5,15-diethynyl-3,7,13,17-tetramethylporphyrin (DEP); an energy shift towards higher photon energy values was obsd. and attributed to charge transfer from the tetrapyrrolic macrocycle to the transition metal terminal groups. Angular dependent NEXAFS characterization of both Pd-ZnDEP and Pt-ZnDEP films deposited on gold allowed to assess that the macromols. grow in ordered layers.
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    Gabrielli, S.; Pellei, M.; Venditti, I.; Fratoddi, I.; Battocchio, C.; Iucci, G.; Schiesaro, I.; Meneghini, C.; Palmieri, A.; Marcantoni, E.; Bagnarelli, L.; Vallesi, R.; Santini, C. Development of new and efficient copper(II) complexes of hexyl bis(pyrazolyl)acetate ligands as catalysts for allylic oxidation. Dalton Trans. 2020, 49, 15622– 15632,  DOI: 10.1039/d0dt02952a
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    Development of new and efficient copper(II) complexes of hexyl bis(pyrazolyl)acetate ligands as catalysts for allylic oxidation
    Gabrielli, Serena; Pellei, Maura; Venditti, Iole; Fratoddi, Ilaria; Battocchio, Chiara; Iucci, Giovanna; Schiesaro, Irene; Meneghini, Carlo; Palmieri, Alessandro; Marcantoni, Enrico; Bagnarelli, Luca; Vallesi, Riccardo; Santini, Carlo
    Dalton Transactions (2020), 49 (44), 15622-15632CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
    In this study, two new hexyl bis(pyrazol-1-yl)acetate ligands and related copper(II) complexes were prepd. and fully characterized in the solid state and in soln. Their electronic and mol. structures were investigated by XPS and near edge X-ray absorption; their ligand mol. structural stability upon coordination to copper was also investigated. The Cu(II) complexes were studied as new catalysts in copper-catalyzed C-H oxidn. for allylic functionalization (the Kharasch-Sosnovsky reaction) avoiding the use of any external reducing agents. Using 5 mol% of these catalysts and tert-butylperoxybenzoate as the oxidant, allylic benzoates were obtained in up to 90% yield: the general reaction time was decreased to 6 h and a 5 to 1 ratio of the alkene and tert-butylperoxybenzoate was used to overcome the two most important limitations on their use in chem.
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    Klein, Joseph C.; Li, Chung Ping; Hercules, David M.; Black, James F.
    Applied Spectroscopy (1984), 38 (5), 729-34CODEN: APSPA4; ISSN:0003-7028.
    Six Cu compds. were analyzed in 3 different x-ray photoelectron spectrometers (AEI-ES200, LHS-10, and HP-5950A), each equipped with a different type of Al Kα x-ray source, to det. the cause of redn. of Cu salts in photoelectron spectrometers. The monochromatic source used in the HP 5950A spectrometer did not cause sample degrdn. Significant sample degrdn. was obsd. in the AEI ES200, which was attributed to the radiative heating from the x-ray gun. The LHS-10 spectrometer, which utilizes a water-cooled x-ray housing, afforded significantly less sample redn. than the AEI ES200 spectrometer.
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    The mol. arrangement in electrodeposited polypyrrole films was studied by means of linear dichroism in the near-edge X-ray absorption fine structure (NEXAFS) spectra measured at the K absorption edges of carbon and nitrogen. It has been found that the change of the exciting radiation incidence from normal to grazing leads to an increase in the intensity of π*-related resonances with simultaneous decrease in the intensity of σ*-related resonances in the spectra. Similar changes in the spectra measured for both absorption edges indicate a pronounced conjugation of π-bonds in the polypyrrole chains in the grown films. Preferential in-plane orientation of pyrrole rings relative to the substrate surface is obsd. for all the deposited films. The linear dichroism is more pronounced at the initial stages of deposition (2D growth) than at later stages characterized by "cauliflower"-like morphol. of the grown film.
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    Nitrogen K-shell excitations in complex molecules and polypyrrole
    Pavlychev, A. A.; Hallmeier, K. H.; Hennig, C.; Hennig, L.; Szargan, R.
    Chemical Physics (1995), 201 (2,3), 547-55CODEN: CMPHC2; ISSN:0301-0104. (Elsevier)
    Exptl. and theor. studies of N K-shell near-edge absorption in complex compds. such as thiourea, benzalaniline, pyrrole, polypyrrole, Et4N+, Bu4N and substituted 2-hydroxy-3-methoxy-benzylidene-aniline compds. were carried out. The quasi-at. model was used to calc. the spectral distribution of oscillator strengths for transitions from the N 1s level to excited discrete and continuum states, to explain general trends in the changes of K-shell excitation spectra and to reveal their relations with chem. bonding of the N atom in the compds. The performed anal. of theor. and exptl. spectra evidences the central role of splitting of an intense N 1s-12p resonance in N K XANES formation in all compds. under study. The influence of the electronic charge transfer, bond conjugation and localization on the energies and intensities of π* and σ* resonances are discussed. The strong connection between interference and chem. bonding effects on the main resonance features of x-ray absorption in the compds. under study is revealed.
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  65. 65
    Franchi, S.; Secchi, V.; Santi, M.; Dettin, M.; Zamuner, A.; Battocchio, C.; Iucci, G. Biofunctionalization of TiO2 surfaces with self-assembling oligopeptides in different pH and Ionic Strength conditions: Charge effects and molecular organization. Mater. Sci. Eng., C 2018, 90, 651– 656,  DOI: 10.1016/j.msec.2018.05.006
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    65
    Biofunctionalization of TiO2 surfaces with self-assembling oligopeptides in different pH and Ionic Strength conditions: Charge effects and molecular organization
    Franchi, S.; Secchi, V.; Santi, M.; Dettin, M.; Zamuner, A.; Battocchio, C.; Iucci, G.
    Materials Science & Engineering, C: Materials for Biological Applications (2018), 90 (), 651-656CODEN: MSCEEE; ISSN:0928-4931. (Elsevier B.V.)
    Self-assembling peptides (SAPs) were investigated by means of XPS and Angular Dependent NEXAFS spectroscopies, with the aim to probe the influence of pH and Ionic Strength conditions on the chem. structure and mol. organization of SAPs anchored on titania surfaces. XPS at the C1s, N1s, O1s core levels allowed to study surfaces and biomol./substrate interfaces. NEXAFS data allowed ascertaining that SAPs mol. structure is preserved upon grafting to the titania surface. Angular Dependent NEXAFS was used to investigate the influence of environmental conditions on the mol. organization behavior. The objective of our study was to establish a set of methodologies for obtaining arrangements of well-organized biomols. on scaffolds surfaces as a basic technol. to develop and optimize cells adhesion and proliferation for tissue engineering applications.
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  66. 66
    Benfatto, M.; Meneghini, C. In Synchrotron Radiation: Basics, Methods and Applications; Mobilio, S., Boscherini, F., Meneghini, C., Eds.; Springer Berlin Heidelberg: Berlin, Heidelberg, 2015; pp 213– 240.
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    Chaboy, J.; Muñoz-Páez, A.; Carrera, F.; Merkling, P.; Marcos, E. S. Ab initiox-ray absorption study of copperK-edge XANES spectra in Cu(II) compounds. Phys. Rev. B: Condens. Matter Mater. Phys. 2005, 71, 134208,  DOI: 10.1103/PhysRevB.71.134208
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    67
    Ab initio x-ray absorption study of copper K-edge XANES spectra in Cu(II) compounds
    Chaboy, Jesus; Munoz-Paez, Adela; Carrera, Flora; Merkling, Patrick; Marcos, Enrique Sanchez
    Physical Review B: Condensed Matter and Materials Physics (2005), 71 (13), 134208/1-134208/7CODEN: PRBMDO; ISSN:1098-0121. (American Physical Society)
    This work reports a theor. study of the x-ray absorption near-edge structure spectra at the Cu K edge in several Cu(II) complexes with N-coordinating ligands showing a square-planar arrangement around metal cation. It is shown that single-channel multiple-scattering calcns. are not able to reproduce the exptl. spectra. The comparison between exptl. data and ab initio computations indicates the need of including the contribution of two electronic configurations (3d9 and 3d10L) to account for a proper description of the final state during the photoabsorption process. The best agreement between theory and expt. is obtained by considering a relative wt. of 68% and 32% for the two absorption channels 3d10L and 3d9, resp.
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  68. 68
    Giorgetti, M.; Guadagnini, L.; Fiddy, S. G.; Santini, C.; Pellei, M. Cu K-edge EXAFS on copper(I) complexes containing dihydridobis(3-nitro-1,2,4-triazol-1-yl)borate and bis(1,2,4-triazol-1-yl)acetate ligand: Evidence for the Cu-O interaction. Polyhedron 2009, 28, 3600– 3606,  DOI: 10.1016/j.poly.2009.07.032
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    68
    Cu K-edge EXAFS on copper(I) complexes containing dihydridobis(3-nitro-1,2,4-triazol-1-yl)borate and bis(1,2,4-triazol-1-yl)acetate ligand: Evidence for the Cu-O interaction
    Giorgetti, Marco; Guadagnini, Lorella; Fiddy, Steven G.; Santini, Carlo; Pellei, Maura
    Polyhedron (2009), 28 (16), 3600-3606CODEN: PLYHDE; ISSN:0277-5387. (Elsevier B.V.)
    X-ray absorption spectroscopy (XAS) has been used to probe the local structure of copper(I) complexes contg. the dihydridobis(3-nitro-1,2,4-triazol-1-yl)borate and the bis(1,2,4-triazol-1-yl)acetate ligands. The material is polycryst. and no crystal structure is available in the literature. The EXAFS anal. has permitted the identification of the local environment of the copper site. Copper is found to be 4-fold coordinated with two sets of Cu-N and Cu-P interactions describing a quasi planar figure. An addnl. coordination is revealed for the copper(I) complex of bis(1,2,4-triazol-1-yl)acetate due to the interaction of the copper with the acetate of the scorpionate ligand. XANES spectra of the studied samples show a resolved pre-edge peak at about 8983 eV which is assigned to the 1s → 4p transition, whose intensities can be explained considering the copper in a 4-fold coordination.
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  69. 69
    Kau, L. S.; Spira-Solomon, D. J.; Penner-Hahn, J. E.; Hodgson, K. O.; Solomon, E. I. X-ray absorption edge determination of the oxidation state and coordination number of copper. Application to the type 3 site in Rhus vernicifera laccase and its reaction with oxygen. J. Am. Chem. Soc. 1987, 109, 6433– 6442,  DOI: 10.1021/ja00255a032
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    69
    X-ray absorption edge determination of the oxidation state and coordination number of copper. Application to the type 3 site in Rhus vernicifera laccase and its reaction with oxygen
    Kau, Lung Shan; Spira-Solomon, Darlene J.; Penner-Hahn, James E.; Hodgson, Keith O.; Solomon, Edward I.
    Journal of the American Chemical Society (1987), 109 (21), 6433-42CODEN: JACSAT; ISSN:0002-7863.
    Cu x-ray absorption edge features of 19 Cu(I) and 40 Cu(II) model complexes were systematically studied and correlated with oxidn. state and geometry. Studies of Cu(I) model complexes with different coordination no. revealed that an 8983-8984-eV peak (assigned as the Cu 1s → 4p transition) could be correlated in energy, shape, and intensity with ligation and site geometry of the Cu(I). These Cu(I) edge features were qual. interpreted with ligand field concepts. Alternatively, no Cu(II) complex exhibited a peak at <8985.0 eV. The limited intensity obsd. in the 8983-8985-eV region for some Cu(II) complexes was assocd. with the tail of an absorption peak at ∼8986 eV which was affected by the covalency of the equatorial ligands. These model studies allowed accurate calibration of a normalized difference edge procedure which is used for the quant. detn. of Cu(I) content in Cu complexes of mixed oxidn. state compn. This normalized difference edge anal. was then used to quant. det. the oxidn. states of the Cu sites in type 2 Cu-depleted (T2D) and native forms of the multi-Cu-contg. oxidase, R. vernicifera laccase. The type 3 (T3) site of T2D laccase was found to be fully reduced and stable to oxidn. by O2 or by 25-fold protein equiv. of ferricyanide, but it could be oxidized by reaction with peroxide. The increase in intensity of the 330-nm absorption feature which resulted from peroxide titrn. of T2D laccase was linearly correlated with the percent of oxidn. of the binuclear Cu site. This correlation indicated that peroxide oxidizes but does not bind to the T3 site. This correlation was used to det. that native laccase, as isolated, contains 22% reduced T3 sites and that all spectral changes obsd. upon peroxide addn. to native laccase can be accounted for by oxidn. of these reduced sites. In the presence of azide and peroxide, further redn. occurs and as many as 40% of the binuclear Cu pairs are stabilized in the reduced state. The importance of these results to previous reports of peroxide binding at the laccase active site is discussed.
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    Fornasini, P. Synchrotron Radiation: Basics, Methods and Applications; Springer Berlin Heidelberg, 2015; pp 181– 211.
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    Noordhuis, P.; Laan, A. C.; van de Born, K.; Losekoot, N.; Kathmann, I.; Peters, G. J. Oxaliplatin activity in selected and unselected human ovarian and colorectal cancer cell lines. Biochem. Pharmacol. 2008, 76, 53– 61,  DOI: 10.1016/j.bcp.2008.04.007
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    Oxaliplatin activity in selected and unselected human ovarian and colorectal cancer cell lines
    Noordhuis, Paul; Laan, Adri C.; van de Born, Kasper; Losekoot, Nienke; Kathmann, Ietje; Peters, Godefridus J.
    Biochemical Pharmacology (2008), 76 (1), 53-61CODEN: BCPCA6; ISSN:0006-2952. (Elsevier)
    Oxaliplatin is used for treatment of colon cancer in combination with 5-fluorouracil or irinotecan. Oxaliplatin has similar, but also different resistant mechanisms as cisplatin. We studied the activity of oxaliplatin in ovarian and colon cancer cells with different resistance patterns to cisplatin. The 40-fold cisplatin-resistant cell line ADDP was only 7.5-fold resistant to oxaliplatin. The gemcitabine-resistant AG6000 cell line, 9-fold resistant to cisplatin, was not cross-resistant. LoVo-175X2, with mutant p53 showed no resistance compared to the empty vector control. However, LoVo-Li, with inactive p53, was 3.6-fold resistant corresponding to decreased accumulation and Pt adducts. Accumulation and DNA adducts formation showed no significant correlation with oxaliplatin sensitivity. Cell cycle distribution after exposure to oxaliplatin showed arrest in G2/M (A2780) or in S-phase (LoVo-92) for wt-p53 cells. ADDP and LoVo-Li showed G1 arrest followed by S-phase arrest and no changes in distribution, resp. The cell cycle related proteins Cyclins A and B1 and (p)CDC25C were marginally affected by oxaliplatin. Expression of hCTR1 was decreased in ADDP, LoVo-Li and AG6000, OCT1 decreased in ADDP and AG6000 and OCT3 in LoVo-175X2, compared to the parental cell lines. In ADDP and LoVo-175X2 ATP7A and B were decreased but were increased in AG6000. From this study it can be concluded that changes in cell cycle distribution were cell line dependent and not related to changes in expression of Cyclin A or B1. Oxaliplatin accumulation was related to hCTR1 and, at low concn., ATP7A to DNA adducts formation while the retention was related to hCTR1, OCT2 and ATP7B.
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    Wersinger, C.; Rebel, G.; Lelong-Rebel, I. Detailed study of the different taurine uptake systems of colon LoVo MDR and non-MDR cell lines. Amino Acids 2000, 19, 667– 685,  DOI: 10.1007/s007260070015
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    Detailed study of the different taurine uptake systems of colon LoVo MDR and non-MDR cell lines
    Wersinger, C.; Rebel, G.; Lelong-Rebel, I. H.
    Amino Acids (2000), 19 (3-4), 667-685CODEN: AACIE6; ISSN:0939-4451. (Springer-Verlag Wien)
    In human, physiol. taurine requirement is partly dependent on nutrition. Study of the human carcinoma LoVo cells shows the presence of a high and a low affinity taurine uptake. Besides them, a diffusion system has been found. A detailed anal. of the properties of the three systems is presented. A comparison of LoVo chemosensitive cells, and LoVo chemoresistant (MDR) cells which overexpress the multidrug transporter P-glycoprotein, shows that the only difference between the two cell types belong to the kinetic properties of the high and low affinity taurine uptake systems.
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    Marzano, C.; Pellei, M.; Colavito, D.; Alidori, S.; Lobbia, G. G.; Gandin, V.; Tisato, F.; Santini, C. Synthesis, characterization, and in vitro antitumor properties of tris(hydroxymethyl)phosphine copper(I) complexes containing the new bis(1,2,4-triazol-1-yl)acetate ligand. J. Med. Chem. 2006, 49, 7317– 7324,  DOI: 10.1021/jm0601248
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    73
    Synthesis, Characterization, and in Vitro Antitumor Properties of Tris(hydroxymethyl)phosphine Copper(I) Complexes Containing the New Bis(1,2,4-triazol-1-yl)acetate Ligand
    Marzano, Cristina; Pellei, Maura; Colavito, Davide; Alidori, Simone; Lobbia, Giancarlo Gioia; Gandin, Valentina; Tisato, Francesco; Santini, Carlo
    Journal of Medicinal Chemistry (2006), 49 (25), 7317-7324CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    The new sodium bis(1,2,4-triazol-1-yl)acetate ligand, Na[HC(CO2)(tz)2], has been prepd. in methanol soln. by using 1,2,4-triazole, dibromoacetic acid and NaOH. Treatment of the [Cu(CH3CN)4][PF6] acceptor with Na[HC(CO2)(tz)2] or Na[HC(CO2)(pzMe2)2] in the presence of the tris(hydroxymethyl)phosphine coligand in methanol/acetonitrile solns. produced unprecedented mononuclear copper(I) complexes of the type [HC(CO2)(tz)2]Cu[P(CH2OH)3]2 (2), [HC(CO2)(pzMe2)2]Cu[P(CH2OH)3]2 (3) and [(CH3CN)2Cu(P(CH2OH)3)2]PF6 (4). These compds. have been characterized by elemental analyses, FTIR, ESI-MS, and multinuclear (1H and 31P) NMR spectral data. The new copper(I) complexes were tested for their cytotoxic properties against a panel of several human tumor cell lines. The results reported here indicate that all the complexes showed in vitro antitumor activity similar or better than that of cisplatin, the most used metal-based antitumor drug. In particular, complex 3 showed IC50 values markedly lower than the ref. compd. against all tumor cell lines. Chemosensitivity tests performed on cisplatin sensitive and resistant cell lines have demonstrated that all these Cu(I) complexes were able to overcome cisplatin resistance, supporting the hypothesis of a different mechanism of action compared to that exhibited by the ref. drug. Flow cytometric anal. on 2008 human ovarian carcinoma cells revealed that complex 3, chosen as the best candidate, induced a marked enlargement of both cell size and granularity and a significant increase in the fraction of G2/M cells that, differently from cisplatin, was not accompanied by the appearance of a relevant sub-G1 fraction. No evidence of caspase-3 activation was detected in cells treated with complex 3. We hypothesize that the cytotoxic activity of the new copper(I) complex may be correlated to its ability to trigger paraptosis, a non-apoptotic mechanism of cell death.
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    Pellei, M.; Gandin, V.; Cimarelli, C.; Quaglia, W.; Mosca, N.; Bagnarelli, L.; Marzano, C.; Santini, C. Syntheses and biological studies of nitroimidazole conjugated heteroscorpionate ligands and related Cu(I) and Cu(II) complexes. J. Inorg. Biochem. 2018, 187, 33– 40,  DOI: 10.1016/j.jinorgbio.2018.07.008
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    74
    Syntheses and biological studies of nitroimidazole conjugated heteroscorpionate ligands and related Cu(I) and Cu(II) complexes
    Pellei, Maura; Gandin, Valentina; Cimarelli, Cristina; Quaglia, Wilma; Mosca, Nello; Bagnarelli, Luca; Marzano, Cristina; Santini, Carlo
    Journal of Inorganic Biochemistry (2018), 187 (), 33-40CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier)
    Cu(I) and Cu(II) complexes of 5-nitroimidazole conjugated heteroscorpionate ligands were synthesized. In particular, the new 2,2-bis(pyrazol-1-yl)-N-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)acetamide ligand (LHMN) was synthesized by direct coupling of preformed side chain acid with 5-nitroimidazole and its coordination chem. was studied towards Cu(I) and Cu(II) acceptors and compared with that of the related 2,2-bis(3,5-dimethyl-1-H-pyrazol-1-yl)-N-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)acetamide ligand (LMeMN). The Cu(II) complexes {[(LMeMN)2Cu]Cl2} and {[(LHMN)2Cu]Cl2} were prepd. by the reaction of CuCl2·2H2O with LHMN or LMeMN ligands in MeOH soln. The water sol. Cu(I) complexes {[(LMeMN)Cu(PTA)2]}(PF6) and {[(LHMN)Cu(PTA)2]}(PF6) were prepd. by the reaction of Cu(MeCN)4PF6 and 1,3,5-triaza-7-phosphaadamantane (PTA) with LHMN or LMeMN ligands in MeCN soln. The new Cu(I) and Cu(II) complexes as well as the corresponding uncoordinated ligands were evaluated for their cytotoxic activity against 2-dimensional monolayer cultures of multiple human cancer cell lines and 3-dimensional-cultured HCT-15 colon cancer spheroids. Morphol. anal. by TEM revealed the induction of a massive cytoplasmic vacuolization consistent with a paraptotic-like cancer cell death.
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    Zanoni, M.; Cortesi, M.; Zamagni, A.; Arienti, C.; Pignatta, S.; Tesei, A. Modeling neoplastic disease with spheroids and organoids. J. Hematol. Oncol. 2020, 13, 97,  DOI: 10.1186/s13045-020-00931-0
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    Modeling neoplastic disease with spheroids and organoids
    Zanoni Michele; Cortesi Michela; Zamagni Alice; Arienti Chiara; Pignatta Sara; Tesei Anna
    Journal of hematology & oncology (2020), 13 (1), 97 ISSN:.
    Cancer is a complex disease in which both genetic defects and microenvironmental components contribute to the development, progression, and metastasization of disease, representing major hurdles in the identification of more effective and safer treatment regimens for patients. Three-dimensional (3D) models are changing the paradigm of preclinical cancer research as they more closely resemble the complex tissue environment and architecture found in clinical tumors than in bidimensional (2D) cell cultures. Among 3D models, spheroids and organoids represent the most versatile and promising models in that they are capable of recapitulating the heterogeneity and pathophysiology of human cancers and of filling the gap between conventional 2D in vitro testing and animal models. Such 3D systems represent a powerful tool for studying cancer biology, enabling us to model the dynamic evolution of neoplastic disease from the early stages to metastatic dissemination and the interactions with the microenvironment. Spheroids and organoids have recently been used in the field of drug discovery and personalized medicine. The combined use of 3D models could potentially improve the robustness and reliability of preclinical research data, reducing the need for animal testing and favoring their transition to clinical practice. In this review, we summarize the recent advances in the use of these 3D systems for cancer modeling, focusing on their innovative translational applications, looking at future challenges, and comparing them with most widely used animal models.
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    Öhrvik, H.; Aaseth, J.; Horn, N. Orchestration of dynamic copper navigation─new and missing pieces. Metallomics 2017, 9, 1204– 1229,  DOI: 10.1039/c7mt00010c
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    76
    Orchestration of dynamic copper navigation - new and missing pieces
    Ohrvik Helena; Aaseth Jan; Horn Nina
    Metallomics : integrated biometal science (2017), 9 (9), 1204-1229 ISSN:.
    A general principle in all cells in the body is that an essential metal - here copper - is taken up at the plasma membrane, directed through cellular compartments for use in specific enzymes and pathways, stored in specific scavenging molecules if in surplus, and finally expelled from the cells. Here we attempt to provide a critical view on key concepts involved in copper transfer across membranes and through compartments in the human body. The focus of this review is on the influence of bioinorganic and thermodynamic rules on the flow in cellular copper networks. Transition of copper from one oxidation state to another will often lead to errant electrons that are highly reactive and prone to form radicals and reactive oxygen or nitrogen species (ROS and RNS). Strict control of potentially toxic oxidative species is an important part of understanding the edge of human copper metabolism. The present review critically covers translocation across simple and complex membranes as well as extracellular and intracellular copper routing. We discuss in depth four tissues with polarized cell barriers - the gut, liver, kidneys, and brain - to illustrate the similarities and differences in transcellular transfer. Copper chaperoning, buffering and binding dynamics to guide the metal to different sites are also covered, while individual molecular interaction kinetics are not detailed. Sorting and targeting mechanisms and principles crucial for correct localisation will also be touched upon.
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  77. 77
    Xu, H. N.; Feng, M.; Nath, K.; Nelson, D.; Roman, J.; Zhao, H.; Lin, Z.; Glickson, J.; Li, L. Z. Optical Redox Imaging of Lonidamine Treatment Response of Melanoma Cells and Xenografts. Mol. Imaging Biol. 2019, 21, 426– 435,  DOI: 10.1007/s11307-018-1258-z
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    77
    Optical Redox Imaging of Lonidamine Treatment Response of Melanoma Cells and Xenografts
    Xu, He N.; Feng, Min; Nath, Kavindra; Nelson, David; Roman, Jeff; Zhao, Huaqing; Lin, Zhenwu; Glickson, Jerry; Li, Lin Z.
    Molecular Imaging and Biology (2019), 21 (3), 426-435CODEN: MIBOCZ; ISSN:1860-2002. (Springer)
    Fluorescence of co-enzyme reduced NAD (NADH) and oxidized flavoproteins (Fp) provides a sensitive measure of the mitochondrial redox state and cellular metab. By imaging NADH and Fp, we investigated the utility of optical redox imaging (ORI) to monitor cellular metab. and detect early metabolic response to cancer drugs. We performed ORI of human melanoma DB-1 cells in culture and DB-1 mouse xenografts to detect the redox response to lonidamine (LND) treatment. For cultured cells, LND treatment for 45 min significantly lowered NADH levels with no significant change in Fp, resulting in a significant increase in the Fp redox ratio (Fp/(NADH+Fp)); 3-h prolonged treatment led to a decrease in NADH and an increase in Fp and a more oxidized redox state compared to control. Significant decrease in the mitochondrial redox capacity of LND-treated cells was obsd. for the first time. For xenografts, 45-min LND treatment resulted in a significant redn. of NADH content, no significant changes in Fp content, and a trend of increase in the Fp redox ratio. Intratumor redox heterogeneity was obsd. in both control and LND-treated groups. Our results support the utility of ORI for evaluating cellular metab. and monitoring early metabolic response to cancer drugs.
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  78. 78
    Nordberg, J.; Arnér, E. S. J. Reactive oxygen species, antioxidants, and the mammalian thioredoxin system1 1This review is based on the licentiate thesis “Thioredoxin reductase-interactions with the redox active compounds 1-chloro-2,4-dinitrobenzene and lipoic acid” by Jonas Nordberg, 2001, Karolinska Institute, Stockholm, ISBN 91-631-1064-4. Free Radical Biol. Med. 2001, 31, 1287– 1312,  DOI: 10.1016/s0891-5849(01)00724-9
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    Reactive oxygen species, antioxidants, and the mammalian thioredoxin system
    Nordberg, Jonas; Arner, Elias S. J.
    Free Radical Biology & Medicine (2001), 31 (11), 1287-1312CODEN: FRBMEH; ISSN:0891-5849. (Elsevier Science Inc.)
    A review. Reactive oxygen species (ROS) are known mediators of intracellular signaling cascades. Excessive prodn. of ROS may, however, lead to oxidative stress, loss of cell function, and ultimately apoptosis or necrosis. A balance between oxidant and antioxidant intracellular systems is hence vital for cell function, regulation, and adaptation to diverse growth conditions. Thioredoxin reductase (TrxR) in conjunction with thioredoxin (Trx) is a ubiquitous oxidoreductase system with antioxidant and redox regulatory roles. In mammals, extracellular forms of Trx also have cytokine-like effects. Mammalian TrxR has a highly reactive active site selenocysteine residue resulting in a profound reductive capacity, reducing several substrates in addn. to Trx. Due to the reactivity of TrxR, the enzyme is inhibited by many clin. used electrophilic compds. including nitrosoureas, aurothioglucose, platinum compds., and retinoic acid derivs. The properties of TrxR in combination with the functions of Trx position this system at the core of cellular thiol redox control and antioxidant defense. In this review, the authors focus on the reactions of the Trx system with ROS mols. and different cellular antioxidant enzymes. The authors summarize the TrxR-catalyzed regeneration of several antioxidant compds., including ascorbic acid (vitamin C), selenium-contg. substances, lipoic acid, and ubiquinone (Q10). The general cellular effects of TrxR inhibition are also discussed. Dinitrohalobenzenes constitute a unique class of immunostimulatory TrxR inhibitors and the authors consider the immunomodulatory effects of dinitrohalobenzene compds. in view of their reactions with the Trx system.
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  • Abstract

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    Scheme 1

    Scheme 1. Synthesis of Ligands 1–4 and Complexes 5–16; Reagents and Conditions: (a) HOCH2CH2OH, H2SO4, 85 °C, 1 h; (b) H2NCH2CH2NH2, CDI, THF, 18 h; (c) HC(pz)2COOH or HC(3,5-Me2pz)2COOH, DMAP, EDCI·HCl,16 h; (d) HC(pz)2COOH or HC(3,5-Me2pz)2COOH, HOBT, EDCI·HCl, DMF, 16 h; (e) PTA, Cu(CH3CN)4PF6, CH3CN, Overnight; (f) PPh3, Cu(CH3CN)4PF6, CH3CN, Overnight; and (g) CuCl2·2H2O, CH3CN, 24 h
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    Figure 1

    Figure 1. C 1s spectra of ligand 4 (A), Cu(II) complex 10 (B), and Cu(I) complex 15 (C) and N 1s spectra of 4 (D) and coordination compounds 10 (E) and 15 (F).

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    Figure 2

    Figure 2. C K-edge (left) and N K-edge (right) NEXAFS spectra of ligand 4 and Cu(II) complexes 10 and 16.

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    Figure 3

    Figure 3. Cu K-edge normalized XANES spectra measured on complexes and reference compounds, shifted for the sake of clarity. Edge energies of Cu(II) complexes 10 and 16 match the edge energy of the CuO reference compound. The edge energy of Cu(I) complex 15 matches the edge energy of Cu2O.

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    Figure 4

    Figure 4. (A) Cu K-edge EXAFS data analysis of complexes 10, 15, and 16 are reported. At the top, the experimental k2χexp(k) (dots) and best fit curves k2χfit(k) (black lines) are presented (vertically shifted for clarity). The middle curves (orange) represent the partial contributions used in the analysis of Cu(II) complex 10 (vertically shifted for clarity) for the sake of the example, and the lowest curve (gray) is the best fit residual k2(χfit – χth). (B) Corresponding FT moduli are shown for experimental k2 weighted EXAFS data (dots) and the best fit (black lines). The FT imaginary (Imm-FT) part of the experimental spectrum, best fit, and partial contributions are shown for complex 10 for the sake of an example. The dashed lines highlight in-phase Imm-FT oscillations for Cu–N and Cu–Cl contributions in Cu(II) complexes 10 and 16. The red arrow points out the structural signal lack in the region of the Cu–Cl shell (red dashed line) likely due to some antiphase structural signals. (C) Local structure around Cu is shown to highlight the neighbor shells involved in the analysis, being R = H (complex 10) or R = CH3 (complex 16) (see Scheme 1) and Y = Cl [Cu(II) complexes 10 and 16] and Y = P [Cu(I) complex 15].

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    Figure 5

    Figure 5. Intracellular copper content after treatment with compounds 14–16. PSN-1 cells were treated for 24 or 36 h with 1 μM copper complexes, and the intracellular copper amount was estimated using GF-AAS analysis. Error bars indicate the standard deviation. *P < 0.1 and **P < 0.01 compared with the control.

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    Figure 6

    Figure 6. (A) Sulfhydryl content in PSN1-treated cancer cells incubated for 24 or 36 h with tested compounds 14–16. The sulfhydryl group amount was determined using the DTNB assay. Error bars indicate the S.D. **P < 0.01 compared with the control. (B) Effect of copper compounds on hydrogen peroxide formation in PSN-1 cells. PSN-1 cells were preincubated in PBS/10 mM glucose medium for 20 min at 37 °C in the presence of 10 μM CM-DCFDA and then treated with 10 μM of tested compounds.

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    Figure 7

    Figure 7. (A) PSN-1 cells were treated for 24 h with IC50 concentrations of tested complexes or CCCP (3 μM). The mitochondrial membrane potential was determined using the Mito-ID membrane potential kit. Data are the means of three independent experiments. Error bars indicate the S.D. *P < 0.1 and **P < 0.01 compared with the control. (B) Hoechst staining of PSN-1 cells incubated for 48 h with IC50 doses of 14, 15, or 16.

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      Nancolas, Bethany; Guo, Lili; Zhou, Rong; Nath, Kavindra; Nelson, David S.; Leeper, Dennis B.; Blair, Ian A.; Glickson, Jerry D.; Halestrap, Andrew P.
      Biochemical Journal (2016), 473 (7), 929-936CODEN: BIJOAK; ISSN:0264-6021. (Portland Press Ltd.)
      Lonidamine (LND) is an anti-tumor drug particularly effective at selectively sensitizing tumors to chemotherapy, hyperthermia and radiotherapy, although its precise mode of action remains unclear. It has been reported to perturb the bioenergetics of cells by inhibiting glycolysis and mitochondrial respiration, whereas indirect evidence suggests it may also inhibit L-lactic acid efflux from cells mediated by members of the proton-linked monocarboxylate transporter (MCT) family and also pyruvate uptake into the mitochondria by the mitochondrial pyruvate carrier (MPC). In the present study, we test these possibilities directly. We demonstrate that LND potently inhibits MPC activity in isolated rat liver mitochondria (Ki 2.5 μM) and co-operatively inhibits L-lactate transport by MCT1, MCT2 and MCT4 expressed in Xenopus laevis oocytes with K0.5 and Hill coeff. values of 36-40 μM and 1.65-1.85 resp. In rat heart mitochondria LND inhibited the MPC with similar potency and uncoupled oxidn. of pyruvate was inhibited more effectively (IC50 ∼ 7 μM) than other substrates including glutamate (IC50 ∼ 20 μM). In isolated DB-1 melanoma cells 1-10 μM LND increased L-lactate output, consistent with MPC inhibition, but higher concns. (150 μM) decreased L-lactate output whereas increasing intracellular [L-lactate] > 5-fold, consistent with MCT inhibition. We conclude that MPC inhibition is the most sensitive anti-tumor target for LND, with addnl. inhibitory effects on MCT-mediated L-lactic acid efflux and glutamine/glutamate oxidn. Together these actions can account for published data on the selective tumor effects of LND on L-lactate, intracellular pH (pHi) and ATP levels that can be partially mimicked by the established MPC and MCT inhibitor α-cyano-4-hydroxycinnamate (CHC).
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    6. 6
      Nath, K.; Nelson, D. S.; Heitjan, D. F.; Leeper, D. B.; Zhou, R.; Glickson, J. D. Lonidamine induces intracellular tumor acidification and ATP depletion in breast, prostate and ovarian cancer xenografts and potentiates response to doxorubicin. NMR Biomed. 2015, 28, 281– 290,  DOI: 10.1002/nbm.3240
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      6
      Lonidamine induces intracellular tumor acidification and ATP depletion in breast, prostate and ovarian cancer xenografts and potentiates response to doxorubicin
      Nath, Kavindra; Nelson, David S.; Heitjan, Daniel F.; Leeper, Dennis B.; Zhou, Rong; Glickson, Jerry D.
      NMR in Biomedicine (2015), 28 (3), 281-290CODEN: NMRBEF; ISSN:0952-3480. (John Wiley & Sons Ltd.)
      We demonstrate that the effects of lonidamine (LND, 100 mg/kg, i.p.) are similar for a no. of xenograft models of human cancer including DB-1 melanoma and HCC1806 breast, BT-474 breast, LNCaP prostate and A2870 ovarian carcinomas. Following treatment with LND, each of these tumors exhibits a rapid decrease in intracellular pH, a small decrease in extracellular pH, a concomitant monotonic decrease in nucleoside triphosphate and an increase in inorg. phosphate over a 2-3 h period. We have previously demonstrated that selective intracellular tumor acidification potentiates response of this melanoma model to melphalan (7.5 mg/kg, i.v.), producing an estd. 89% cell kill based on tumor growth delay anal. We now show that, in both DB-1 melanoma and HCC1806 breast carcinoma, LND potentiates response to doxorubicin, producing 95% cell kill in DB-1 melanoma at 7.5 mg/kg, i.v. doxorubicin and 98% cell kill at 10.0 mg/kg doxorubicin, and producing a 95% cell kill in HCC1806 breast carcinoma at 12.0 mg/kg doxorubicin. Potentiation of doxorubicin may result from cation trapping of the weakly basic anthracycline. Recent experience with the clin. treatment of melanoma and other forms of human cancer suggests that these diseases will probably not be cured by a single therapeutic procedure other than surgery. A multimodality therapeutic approach will be required. As a potent modulator of tumor response to N-mustards and anthracyclines as well as tumor thermo- and radiosensitivity, LND promises to play an important clin. role in the management and possible complete local control of a no. of prevalent forms of human cancer. Copyright © 2014 John Wiley & Sons, Ltd.
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    7. 7
      Ravagnan, L.; Marzo, I.; Costantini, P.; Susin, S. A.; Zamzami, N.; Petit, P. X.; Hirsch, F.; Goulbern, M.; Poupon, M.-F.; Miccoli, L.; Xie, Z.; Reed, J. C.; Kroemer, G. Lonidamine triggers apoptosis via a direct, Bcl-2-inhibited effect on the mitochondrial permeability transition pore. Oncogene 1999, 18, 2537– 2546,  DOI: 10.1038/sj.onc.1202625
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      7
      Lonidamine triggers apoptosis via a direct, Bcl-2-inhibited effect on the mitochondrial permeability transition pore
      Ravagnan, Luigi; Marzo, Isabel; Costantini, Paola; Susin, Santos A.; Zamzami, Naoufal; Petit, Patrice X.; Hirsch, Franqois; Goulbern, Marc; Poupon, Marie-France; Miccoli, Laurent; Xie, Zhihua; Reed, John C.; Kroemer, Guido
      Oncogene (1999), 18 (16), 2537-2546CODEN: ONCNES; ISSN:0950-9232. (Stockton Press)
      The mol. mode of action of lonidamine, a therapeutic agent employed in cancer chemotherapy, has been elusive. Here we provide evidence that lonidamine (LND) acts on mitochondria to induce apoptosis. LND provokes a disruption of the mitochondrial transmembrane potential which precedes signs of nuclear apoptosis and cytolysis. The mitochondrial and cytocidal effects of LND are not prevented by inhibitors of caspases or of mRNA or protein synthesis. However, they are prevented by transfection-enforced overexpression of Bcl-2, an oncoprotein which inhibits apoptosis by stabilizing the mitochondrial membrane barrier function. Accordingly, the cell death-inducing effect of LND is amplified by simultaneous addn. of PK11195, an isoquinoline ligand of the peripheral benzodiazepine receptor which antagonizes the cytoprotective effect of Bcl-2. When added to isolated nuclei, LND fails to provoke DNA degrdn. unless mitochondria are added simultaneously. In isolated mitochondria, LND causes the dissipation of the mitochondrial inner transmembrane potential and the release of apoptogenic factors capable of inducing nuclear apoptosis in vitro. Thus the mitochondrion is the subcellular target of LND. All effects of LND on isolated mitochondria are counteracted by cyclosporin A, an inhibitor of the mitochondrial PT pore. We therefore tested the effect of LND on the purified PT pore reconstituted into liposomes. LND permeabilizes liposomal membranes contg. the PT pore. This effect is prevented by addn. of recombinant Bcl-2 protein but not by a mutant Bcl-2 protein that has lost its apoptosis-inhibitory function. Altogether these data indicate that LND represents a novel type of anti-cancer agent which induces apoptosis via a direct effect on the mitochondrial PT pore.
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    8. 8
      Crompton, M. The mitochondrial permeability transition pore and its role in cell death. Biochem. J. 1999, 341, 233– 249,  DOI: 10.1042/bj3410233
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      8
      The mitochondrial permeability transition pore and its role in cell death
      Crompton, Martin
      Biochemical Journal (1999), 341 (2), 233-249CODEN: BIJOAK; ISSN:0264-6021. (Portland Press Ltd.)
      A review, with ∼208 refs. This article reviews the involvement of the mitochondrial permeability transition pore in necrotic and apoptotic cell death. The pore is formed from a complex of the voltage-dependent anion channel (VDAC), the adenine nucleotide translocase and cyclophilin-D (CyP-D) at contact sites between the mitochondrial outer and inner membranes. In vitro, under pseudopathol. conditions of oxidative stress, relatively high Ca2+ and low ATP, the complex flickers into an open-pore state allowing free diffusion of low-Mr solutes across the inner membrane. These conditions correspond to those that unfold during tissue ischemia and reperfusion, suggesting that pore opening may be an important factor in the pathogenesis of necrotic cell death following ischemia/reperfusion. Evidence that the pore does open during ischemia/reperfusion is discussed. There are also strong indications that the VDAC-adenine nucleotide translocase-CyP-D complex can recruit a no. of other proteins, including Bax, and that the complex is utilized in some capacity during apoptosis. The apoptotic pathway is amplified by the release of apoptogenic proteins from the mitochondrial inter-membrane space, including cytochrome c, apoptosis-inducing factor and some procaspases. Current evidence that the pore complex is involved in outer-membrane rupture and release of these proteins during programmed cell death is reviewed, along with indications that transient pore opening may provoke "accidental" apoptosis.
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    9. 9
      Rosbe, K. W.; Brann, T. W.; Holden, S. A.; Teicher, B. A.; Frei, E. Effect of Lonidamine on the cytotoxicity of four alkylating agents in vitro. Cancer Chemother. Pharmacol. 1989, 25, 32– 36,  DOI: 10.1007/bf00694335
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      9
      Effect of lonidamine on the cytotoxicity of four alkylating agents in vitro
      Rosbe, Kristina W.; Brann, Terrence W.; Holden, Sylvia A.; Teicher, Beverly A.; Frei, Emil, III
      Cancer Chemotherapy and Pharmacology (1989), 25 (1), 32-6CODEN: CCPHDZ; ISSN:0344-5704.
      The authors examd. the ability of lonidamine, which has been described as an inhibitor of cellular respiration and glycolysis, to enhance the cytotoxicity of alkylating agents to MCF-7 human breast carcinoma cells. Lonidamine was increasingly cytotoxic to MCF-7 cells with increasing time of exposure. With a 12-h exposure, the IC50 for lonidamine was about 365 μM, and with a 24-h exposure it was about 170 μM. A drug concn. of 250 μM was chosen for use in the drug combination studies. Lonidamine appeared to have a dose-modifying effect on cisplatin (CDDP), producing increasingly supraadditive cell kill with increasing CDDP concn. Lonidamine also appeared to have a dose-modifying effect on melphalan cytotoxicity in the melphalan concn. range of 100-500 μM. At concns of 10-100 μM melphalan, the drug combination survival after 1 h exposure fell within the envelope of additivity for the 2 agents. However, maintaining the presence of lonidamine for an addnl. 12 h increased the effect such that the combination was supraadditive over the entire concn. range of melphalan. Simultaneous exposure to 4-hydroperoxycyclophosphamide (4-HC) and lonidamine for 1 h resulted in greater that additive cell kill, and extending the lonidamine exposure period such that lonidamine was present during and 12 h after 4-HC treatment further increased this effect. Lonidamine had a moderate effect of the cytotoxicity of carmustine (BCNU) with a 1 h simultaneous exposure; however, this treatment combination reached greater than additive cytotoxicity only at the highest concn. of BCNU tested. Extending the lonidamine exposure time for an addnl. 12 h resulted in supraaditive cell kill over the BCNU concn. range. Therefore, when lonidamine was present during exposure to the alkylating agent and its presence was then extended for an addnl. 12 h, a synergistic cell kill was produced with all 4 alkylating agents tested.
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    10. 10
      Angioli, R.; Janicek, M.; Sevin, B.; Estape, R.; Averette, H.; Koechli, O.; Untch, M.; Penalver, M. Use of lonidamine to potentiate the effect of cisplatin and carboplatin on platinum resistant human ovarian cancer cells. Internet J. Oncol. 1997, 11, 777– 780,  DOI: 10.3892/ijo.11.4.777
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      There is no corresponding record for this reference.
    11. 11
      Chen, H.; Chen, F.; Hu, W.; Gou, S. Effective platinum(IV) prodrugs conjugated with lonidamine as a functional group working on the mitochondria. J. Inorg. Biochem. 2018, 180, 119– 128,  DOI: 10.1016/j.jinorgbio.2017.11.017
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      11
      Effective platinum(IV) prodrugs conjugated with lonidamine as a functional group working on the mitochondria
      Chen, Hong; Chen, Feihong; Hu, Weiwei; Gou, Shaohua
      Journal of Inorganic Biochemistry (2018), 180 (), 119-128CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier)
      Platinum-based anticancer drugs are one of the most widely used anticancer chemotherapeutics in oncol. Lonidamine (LND) could increase the response of human tumor cells to platinum(II) drugs in preclin. studies by working on the mitochondria. Herein, five platinum(IV) prodrugs conjugated with their potentiator LND are prepd., and most of the target complexes achieve improved anticancer activities compared with their platinum(II) precursors. Notably, Pt(NH3)2(LND)Cl3 (complex 1) derived from cisplatin achieve significantly improved anticancer activities against LNCaP cells and could trigger cancer cell death via an apoptotic pathway and the cell cycle arrest mainly at S phases. And the induction of apoptosis by complex 1 in LNCaP cells is closely assocd. with mitochondrial function disruption and reactive oxygen species (ROS) accumulation. Moreover, it is possessed of the ability to overcome cisplatin-resistance. Further research revealed that complex 1 could be easily reduced to release its platinum(II) precursor and axial ligand by ascorbic acid. All the results provide evidence to support the design strategy of conjugating platinum complexes with its potentiator to improve their anticancer effect.
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    12. 12
      Okulova, Y. N.; Zenin, I. V.; Shutkov, I. A.; Kirsanov, K. I.; Kovaleva, O. N.; Lesovaya, E. A.; Fetisov, T. I.; Milaeva, E. R.; Nazarov, A. A. Antiproliferative activity of Pt(IV) complexes with lonidamine and bexarotene ligands attached via succinate-ethylenediamine linker. Inorg. Chim. Acta 2019, 495, 119010,  DOI: 10.1016/j.ica.2019.119010
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      12
      Antiproliferative activity of Pt(IV) complexes with lonidamine and bexarotene ligands attached via succinate-ethylenediamine linker
      Okulova, Y. N.; Zenin, I. V.; Shutkov, I. A.; Kirsanov, K. I.; Kovaleva, O. N.; Lesovaya, E. A.; Fetisov, T. I.; Milaeva, E. R.; Nazarov, A. A.
      Inorganica Chimica Acta (2019), 495 (), 119010CODEN: ICHAA3; ISSN:0020-1693. (Elsevier B.V.)
      The authors present the synthesis and cytotoxic potencies of new Pt(IV) complexes with lonidamine and bexarotene ligand tethered to Pt-center via a succinate-ethylenediamine linker. The in vitro results for a series of complexes with cisplatin, dichloride(ethane-1,2-diamine)platinum(II), or oxaliplatin core indicate that the addn. to the structure lonidamine or bexarotene moiety can confer activity or selectivity of Pt(IV) complexes.
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    13. 13
      Nosova, Y. N.; Foteeva, L. S.; Zenin, I. V.; Fetisov, T. I.; Kirsanov, K. I.; Yakubovskaya, M. G.; Antonenko, T. A.; Tafeenko, V. A.; Aslanov, L. A.; Lobas, A. A.; Gorshkov, M. V.; Galanski, M.; Keppler, B. K.; Timerbaev, A. R.; Milaeva, E. R.; Nazarov, A. A. Enhancing the Cytotoxic Activity of Anticancer Pt IV Complexes by Introduction of Lonidamine as an Axial Ligand. Eur. J. Med. Chem. 2017, 2017, 1785– 1791,  DOI: 10.1002/ejic.201600857
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      There is no corresponding record for this reference.
    14. 14
      Ruttala, H. B.; Ramasamy, T.; Poudel, B. K.; Ruttala, R. R. T.; Jin, S. G.; Choi, H.-G.; Ku, S.-K.; Yong, C. S.; Kim, J. O. Multi-responsive albumin-lonidamine conjugated hybridized gold nanoparticle as a combined photothermal-chemotherapy for synergistic tumor ablation. Acta Biomater. 2020, 101, 531– 543,  DOI: 10.1016/j.actbio.2019.11.003
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      14
      Multi-responsive albumin-lonidamine conjugated hybridized gold nanoparticle as a combined photothermal-chemotherapy for synergistic tumor ablation
      Ruttala, Hima Bindu; Ramasamy, Thiruganesh; Poudel, Bijay Kumar; Ruttala, Raghu Ram Teja; Jin, Sung Giu; Choi, Han-Gon; Ku, Sae-Kwang; Yong, Chul Soon; Kim, Jong Oh
      Acta Biomaterialia (2020), 101 (), 531-543CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)
      Herein, we developed a multifunctional nanoplatform based on the nanoassembly of gold nanoparticles (GNP) conjugated with lonidamine (LND) and aptamer AS1411 (AS-LAGN) as an effective cancer treatment. Conjugating AS1411 aptamer on the surface of the nanoparticle significantly improved particle accumulation in cancer cells via specific affinity toward the nucleolin receptors. In vitro study clearly revealed that laser irradn.-based hyperthermia effect enhanced the chemotherapeutic effects of LND. Combinational treatment modalities revealed significant apoptosis with higher cell killing effect due to increased ROS prodn. and inhibition of cell migration. GNP's ability to convert the excited state photon energy into thermal heat enabled synergistic photothermal/chemotherapy with improved therapeutic efficacy in animal models. Moreover, immunohistochem. staining assays confirmed the ability of AS-LAGN to induce cellular apoptosis/necrosis and ablation in tumor tissues, without causing evident damages to the surrounding healthy tissues. Altogether, this AS-LAGN nanoplatform could be a promising strategy for mitochondria-based cancer treatment. We have designed a facile biodegradable multifunctional nanocarrier system to target the mitochondria, the major "power house" of the cancer cells. We have constructed a multifunctional nanoassembly of protein coronated gold nanoparticles (GNP) conjugated with lonidamine (LND) and aptamer AS1411 (AS-LAGN) as an effective combination of phototherapy with chemotherapy for cancer treatment. The LND was conjugated with albumin which was in turn conjugated to GNP via redox-liable disulfide linkage to generate oxidative stress and ROS to kill cancer cells. Consistently, AS-LAGN showed enhanced antitumor efficacy in xenograft tumor model with remarkable tumor regression property.
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    15. 15
      Qin, Q.-P.; Liu, Y.-C.; Wang, H.-L.; Qin, J.-L.; Cheng, F.-J.; Tang, S.-F.; Liang, H. Synthesis and antitumor mechanisms of a copper(ii) complex of anthracene-9-imidazoline hydrazone (9-AIH). Metallomics 2015, 7, 1124– 1136,  DOI: 10.1039/C5MT00027K
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      15
      Synthesis and antitumor mechanisms of a copper(II) complex of anthracene-9-imidazoline hydrazone (9-AIH)
      Qin, Qi-Pin; Liu, Yan-Cheng; Wang, Hai-Lu; Qin, Jiao-Lan; Cheng, Feng-Jie; Tang, Shang-Feng; Liang, Hong
      Metallomics (2015), 7 (7), 1124-1136CODEN: METAJS; ISSN:1756-591X. (Royal Society of Chemistry)
      A new anthracycline deriv., anthracene-9-imidazoline hydrazone (9-AIH), was synthesized and selected as an antitumor ligand to afford a copper(II) complex of 9-AIH, cis-[CuIICl2(9-AIH)] (1). Complex 1 was structurally characterized by IR, elemental anal., ESI-MS and single crystal X-ray diffraction anal. By MTT assay, it was revealed that 1 showed overall a higher in vitro cytotoxicity than 9-AIH towards a panel of human tumor cell lines, with IC50 values from 0.94-3.68 μM, in which the BEL-7404 cell line was the most sensitive to 1. By spectral analyses and gel electrophoresis, the DNA binding affinity of 9-AIH and 1 was detd. 9-AIH was suggested to bind with DNA in an intercalative mode, with a quenching const. of 1.04 × 104 M-1 on the EB-DNA complex. While for 1, both intercalative and covalent binding modes were suggested. By flow cytometry, 1 was found to block the cell cycle of BEL-7404 cells in a dose-dependent mode, in which it induced the G2/M phase arrest at 0.5 μM and induced the S phase arrest at higher concns. of 1.0 or 2.0 μM. From the cellular morphol. observations under different fluorescence probe staining, a dose-dependent manner of 1 to induce cell apoptosis in the late stage was suggested. Comparatively, equiv. apoptotic cells, resp., in the early and late stages were found when incubated with 2.0 μM of 9-AIH. The mitochondrial membrane potential measured by JC-1 staining and the ROS generation in cells detected using a DCFH-DA probe suggested that the cell apoptosis induced by 1 might undergo the ROS-related mitochondrial pathway. Accordingly, the mutant p53 expression was found to be suppressed and the caspase cascade (caspase-9/3) was consequently activated by 1. This action mechanism for 1 in the BEL-7404 cells was unique and was not found in the presence of 9-AIH under the same conditions, indicating their different antitumor mechanism. Furthermore, the in vivo acute toxicity of 1 tested on mice indicated that 1 should be a high cytotoxic antitumor agent, with the LD50 value in the range of 32-45 mg kg-1, which is much higher than that of 9-AIH. From the above results, the central Cu(II) of 1 in the coordinated mode with 9-AIH was believed to play a key role in exerting both the high cytotoxicity and the effective antitumor mechanism.
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    16. 16
      Raman, N.; Jeyamurugan, R.; Senthilkumar, R.; Rajkapoor, B.; Franzblau, S. G. In vivo and in vitro evaluation of highly specific thiolate carrier group copper(II) and zinc(II) complexes on Ehrlich ascites carcinoma tumor model. Eur. J. Med. Chem. 2010, 45, 5438– 5451,  DOI: 10.1016/j.ejmech.2010.09.004
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      16
      In vivo and in vitro evaluation of highly specific thiolate carrier group copper(II) and zinc(II) complexes on Ehrlich ascites carcinoma tumor model
      Raman, N.; Jeyamurugan, R.; Senthilkumar, R.; Rajkapoor, B.; Franzblau, Scott G.
      European Journal of Medicinal Chemistry (2010), 45 (11), 5438-5451CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
      A new series of copper(II) and zinc(II) benzene-1,2-dithiol complexes with novel Schiff base ligands have been prepd. The Schiff base ligands are derived from the reaction of 3-(3-phenyl-allylidene)-pentane-2,4-dione with para substituted aniline. Their structures have been established by anal. and spectral data. The higher ε and low A‖ values together with pos. redn. potentials for these copper complexes suggest that they can mimic the functional properties of naturally occurring proteins. In vivo and in vitro antitumor functions of the complexes against Ehrlich ascites carcinoma tumor model have been studied. The min. inhibitory concn. of the complexes has also been studied against Mycobacterium tuberculosis strain H37Rv. These complexes exhibit significant antitumor, cytotoxic and antituberculosis activity.
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    17. 17
      Palanimuthu, D.; Shinde, S. V.; Somasundaram, K.; Samuelson, A. G. In Vitro and in Vivo Anticancer Activity of Copper Bis(thiosemicarbazone) Complexes. J. Med. Chem. 2013, 56, 722– 734,  DOI: 10.1021/jm300938r
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      17
      In Vitro and in Vivo Anticancer Activity of Copper Bis(thiosemicarbazone) Complexes
      Palanimuthu, Duraippandi; Shinde, Sridevi Vijay; Somasundaram, Kumaravel; Samuelson, Ashoka G.
      Journal of Medicinal Chemistry (2013), 56 (3), 722-734CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Neutral and cationic copper bis(thiosemicarbazone) complexes bearing Me, Ph, and H, on the diketo-backbone of the ligand were synthesized. All of them were characterized by spectroscopic methods and in three cases by x-ray crystallog. In vitro cytotoxicity studies revealed that they are cytotoxic, unlike the corresponding Zn complexes. Copper complexes Cu(GTSC) and Cu(GTSCHCl) derived from glyoxal bis(4-methyl-4-phenyl-3-thiosemicarbazone) (GTSCH2) are the most cytotoxic complexes against various human cancer cell lines, with a potency similar to that of the anticancer drug adriamycin and up to 1000 fold higher than that of the corresponding Zn complex. Tritiated thymidine incorporation assay revealed that Cu(GTSC) and Cu(GTSCHCl) inhibit DNA synthesis substantially. Cell cycle analyses showed that Cu(GTSC) and Cu(GTSCHCl) induce apoptosis in HCT116 cells. The Cu(GTSCHCl) complex caused distinct DNA cleavage and Topo IIα inhibition unlike that for Cu(GTSC). In vivo administration of Cu(GTSC) significantly inhibits tumor growth in HCT116 xenografts in nude mice.
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    18. 18
      Montagner, D.; Fresch, B.; Browne, K.; Gandin, V.; Erxleben, A. A Cu(ii) complex targeting the translocator protein: in vitro and in vivo antitumor potential and mechanistic insights. Chem. Commun. 2017, 53, 134– 137,  DOI: 10.1039/C6CC08100B
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      18
      A Cu(II) complex targeting the translocator protein: in vitro and in vivo antitumor potential and mechanistic insights
      Montagner, D.; Fresch, B.; Browne, K.; Gandin, V.; Erxleben, A.
      Chemical Communications (Cambridge, United Kingdom) (2017), 53 (1), 134-137CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      A new Cu-based anticancer metallodrug which targets the translocator protein is reported. [CuBr2(TZ6)] elicits a remarkable in vitro cytotoxicity in sensitive and multidrug resistant cell lines and induces a 98% redn. of tumor mass in a murine tumor model. Target binding was studied by exptl. and computational methods.
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    19. 19
      Laws, K.; Bineva-Todd, G.; Eskandari, A.; Lu, C.; O’Reilly, N.; Suntharalingam, K. A Copper(II) Phenanthroline Metallopeptide That Targets and Disrupts Mitochondrial Function in Breast Cancer Stem Cells. Angew. Chem., Int. Ed. 2018, 57, 287– 291,  DOI: 10.1002/ange.201710910
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      19
      A Copper(II) Phenanthroline Metallopeptide That Targets and Disrupts Mitochondrial Function in Breast Cancer Stem Cells
      Laws, Kristine; Bineva-Todd, Ganka; Eskandari, Arvin; Lu, Chunxin; O'Reilly, Nicola; Suntharalingam, Kogularamanan
      Angewandte Chemie, International Edition (2018), 57 (1), 287-291CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The breast cancer stem cell (CSC) and bulk breast cancer cell potency of a series of metallopeptides contg. dichloro(1,10-phenanthroline)copper(II) and various organelle-targeting peptide sequences is reported. The mitochondria-targeting metallopeptide 1 exploits the higher mitochondrial load in breast CSCs over the corresponding non-CSCs and the vulnerability of breast CSCs to mitochondrial damage to potently and selectively kill breast CSCs. Strikingly, 1 reduces the formation and size of mammospheres to a greater extent than salinomycin, an established CSC-potent agent. Mechanistic studies show that 1 enters CSC mitochondria, induces mitochondrial dysfunction, generates reactive oxygen species (ROS), activates JNK and p38 pathways, and prompts apoptosis. To the best of our knowledge, 1 is the first metallopeptide to selectivity kill breast CSCs in vitro.
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    20. 20
      Mahendiran, D.; Kumar, R. S.; Viswanathan, V.; Velmurugan, D.; Rahiman, A. K. In vitro and in vivo anti-proliferative evaluation of bis(4′-(4-tolyl)-2,2′:6′,2″-terpyridine)copper(II) complex against Ehrlich ascites carcinoma tumors. JBIC, J. Biol. Inorg. Chem. 2017, 22, 1109– 1122,  DOI: 10.1007/s00775-017-1488-6
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      In vitro and in vivo anti-proliferative evaluation of bis(4'-(4-tolyl)-2,2':6',2''-terpyridine)copper(II) complex against Ehrlich ascites carcinoma tumors
      Mahendiran, Dharmasivam; Kumar, Raju Senthil; Viswanathan, Vijayan; Velmurugan, Devadasan; Rahiman, Aziz Kalilur
      JBIC, Journal of Biological Inorganic Chemistry (2017), 22 (7), 1109-1122CODEN: JJBCFA; ISSN:0949-8257. (Springer)
      The bis(4'-(4-tolyl)-2,2':6',2''-terpyridine)copper(II) complex [Cu(ttpy)2]Cl2 was synthesized and authenticated by single crystal anal., which shows distorted octahedral geometry around copper(II) ion. The crystal packing is stabilized by C-H···π inter and intramol. interactions. The complex was found to be lipophilic as detd. by shake-flask method. In vitro cytotoxicity of the complex was tested against Ehrlich ascites carcinoma (EAC) and L6 myotube cell lines. The complex exhibit potent cytotoxicity with respect to the com. available anticancer drug cisplatin. Hoechst 33258, AO/EB and PI (flow cytometry) staining methods suggest that the complex can induce apoptosis in EAC cells. Cell cycle analyses also support the induced apoptosis. Cellular uptake studies revealed that the complex can go into the cytoplasm and accumulate in the cell nuclei. The complex induces EAC cell apoptosis through a ROS-mediated mitochondrial pathway by activating caspase 3 and caspase 7 and regulates the Bcl-2 family proteins. In vivo study of the complex was validated against the animal tumor growth (EAC) cell in Swiss albino mice.
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    21. 21
      Becco, L.; García-Ramos, J. C.; Azuara, L. R.; Gambino, D.; Garat, B. Analysis of the DNA Interaction of Copper Compounds Belonging to the Casiopeínas Antitumoral Series. Biol. Trace Elem. Res. 2014, 161, 210– 215,  DOI: 10.1007/s12011-014-0098-1
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      Analysis of the DNA Interaction of Copper Compounds Belonging to the Casiopei´nas Antitumoral Series
      Becco, Lorena; Garcia-Ramos, Juan Carlos; Azuara, Lena Ruiz; Gambino, Dinorah; Garat, Beatriz
      Biological Trace Element Research (2014), 161 (2), 210-215CODEN: BTERDG; ISSN:0163-4984. (Springer)
      Casiopei´nas are mixed-chelate copper complexes with antitumor tested potential. Their activity, both in vitro and in vivo, as antiproliferative, cytotoxic, and genotoxic drugs has been assessed. Biol. results of these copper compds. have deserved some of them entering clin. trials. Significant efforts have been devoted to the in-depth identification of their mechanism of action. Using gel electrophoresis anal., we have previously shown that the interaction of the Casiopei´nas Cas II-gly, [Cu(4,7-dimethyl-1,10-phenanthroline)(glycinate)]NO3 with DNA, triggers the cleavage of the biomol. by a free radical mechanism. In this work, we further study the behavior of different complexes of the same Casiopei´nas series also including glycinate as co-ligand {Cas VI-gly (5,6 dimethyl-1,10-phenanthroline glycinato copper(II) nitrate), Cas VII-gly (1,10-phenanthroline glycinato copper(II) nitrate), and Cas IX-gly (2,2'-bipyridine glycinato copper(II) nitrate)} and of a Casiopei´nas with a different co-ligand (Cas III-Cs; 4,7-dimethyl-1,10-phenanthroline salicylaldehydato-copper(II) nitrate). While all of them produce DNA degrdn., the performance in the presence of a radical scavenger suggests the existence of differences in their mechanism of interaction with DNA.
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    22. 22
      Gandin, V.; Ceresa, C.; Esposito, G.; Indraccolo, S.; Porchia, M.; Tisato, F.; Santini, C.; Pellei, M.; Marzano, C. Therapeutic potential of the phosphino Cu(I) complex (HydroCuP) in the treatment of solid tumors. Sci. Rep. 2017, 7, 13936,  DOI: 10.1038/s41598-017-13698-1
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      Therapeutic potential of the phosphino Cu(I) complex (HydroCuP) in the treatment of solid tumors
      Gandin Valentina; Marzano Cristina; Ceresa Cecilia; Esposito Giovanni; Indraccolo Stefano; Porchia Marina; Tisato Francesco; Santini Carlo; Pellei Maura
      Scientific reports (2017), 7 (1), 13936 ISSN:.
      [Cu(thp)4][PF6] (HydroCuP) is a phosphino copper(I) complex highly soluble and stable in physiological media that has been developed as a possible viable alternative to platinum-based drugs for anticancer therapy. HydroCuP potently inhibited the growth of human cancer cells derived from solid tumors by inducing endoplasmatic reticulum (ER) stress thus leading to cell death through paraptosis with a preferential efficacy against cancer rather than non-cancer cells. Aim of the present study was to assess the therapeutic potential of HydroCuP in vivo, in syngenic and xenograft murine models of solid tumors by triggering the Unfolded Protein Response (UPR) pathway. With respect to platinum drugs, HydroCuP induced a markedly higher reduction of tumor growth associated with minimal animal toxicity. In human colorectal cancer xenografts, chemotherapy with HydroCuP was extremely effective in both oxaliplatin-sensitive and resistant models. The favorable in vivo tolerability of HydroCuP was also correlated to an encouraging biodistribution profile. Additionally, no signs of drug-related neurotoxicity and nephrotoxicity were observed. Altogether, these results demonstrate that HydroCuP appears worth of further investigation to evaluate its therapeutic activity towards a broad spectrum of solid malignancies.
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    23. 23
      Gandin, V.; Pellei, M.; Tisato, F.; Porchia, M.; Santini, C.; Marzano, C. A novel copper complex induces paraptosis in colon cancer cells via the activation of ER stress signalling. J. Cell. Mol. Med. 2012, 16, 142– 151,  DOI: 10.1111/j.1582-4934.2011.01292.x
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      23
      A novel copper complex induces paraptosis in colon cancer cells via the activation of ER stress signalling
      Gandin, Valentina; Pellei, Maura; Tisato, Francesco; Porchia, Marina; Santini, Carlo; Marzano, Cristina
      Journal of Cellular and Molecular Medicine (2012), 16 (1), 142-151CODEN: JCMMC9; ISSN:1582-4934. (Wiley-Blackwell)
      Platinum anticancer drugs have been used for three decades despite their serious side effects and the emerging of resistance phenomena. Recently, a phosphine copper(I) complex, [Cu(thp)4][PF6] (CP), gained special attention because of its strong antiproliferative effects. CP killed human colon cancer cells more efficiently than cisplatin and oxaliplatin and it overcame platinum drug resistance. CP preferentially reduced cancer cell viability whereas non-tumor cells were poorly affected. Colon cancer cells died via a programmed cell death whose transduction pathways were characterized by the absence of hallmarks of apoptosis. The inhibition of 26S proteasome activities induced by CP caused intracellular accumulation of polyubiquitinated proteins and the functional suppression of the ubiquitin-proteasome pathway thus triggering endoplasmic reticulum stress. These data, providing a mechanistic characterization of CP-induced cancer cell death, shed light on the signaling pathways involved in paraptosis thus offering a new tool to overcome apoptosis-resistance in colon cancer cells.
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    24. 24
      Gandin, V.; Tisato, F.; Dolmella, A.; Pellei, M.; Santini, C.; Giorgetti, M.; Marzano, C.; Porchia, M. In Vitro and in Vivo Anticancer Activity of Copper(I) Complexes with Homoscorpionate Tridentate Tris(pyrazolyl)borate and Auxiliary Monodentate Phosphine Ligands. J. Med. Chem. 2014, 57, 4745– 4760,  DOI: 10.1021/jm500279x
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      24
      In Vitro and in Vivo Anticancer Activity of Copper(I) Complexes with Homoscorpionate Tridentate Tris(pyrazolyl)borate and Auxiliary Monodentate Phosphine Ligands
      Gandin, Valentina; Tisato, Francesco; Dolmella, Alessandro; Pellei, Maura; Santini, Carlo; Giorgetti, Marco; Marzano, Cristina; Porchia, Marina
      Journal of Medicinal Chemistry (2014), 57 (11), 4745-4760CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Tetrahedral copper(I) TpCuP complexes 1-15, where Tp is a N,N,N-tris(azolyl)borate and P is a tertiary phosphine, have been synthesized and characterized by NMR, ESI-MS, and XAS-EXAFS, and x-ray diffraction analyses on the representative complexes 1 and 10, resp. All copper(I) complexes were evaluated for their antiproliferative activity against a panel of human cancer cell lines (including cisplatin and multidrug-resistant sublines). The two most effective complexes [HB(pz)3]Cu(PCN), 1, and [HB(pz)3]Cu(PTA), 2, showed selectivity toward tumor vs normal cells, inhibition of 26S proteasome activity assocd. with endoplasmic reticulum (ER) stress, and unfolded protein response (UPR) activation. No biochem. hallmarks of apoptosis were detected, and morphol. studies revealed an extensive cytoplasmic vacuolization coherently with a paraptosis-like cell death mechanism. Finally, the antitumor efficacy of complex 1 was validated in the murine Lewis Lung Carcinoma (LLC) model.
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      Erxleben, A. Interactions of copper complexes with nucleic acids. Coord. Chem. Rev. 2018, 360, 92– 121,  DOI: 10.1016/j.ccr.2018.01.008
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      25
      Interactions of copper complexes with nucleic acids
      Erxleben, Andrea
      Coordination Chemistry Reviews (2018), 360 (), 92-121CODEN: CCHRAM; ISSN:0010-8545. (Elsevier B.V.)
      A review. Covalent or non-covalent interactions with DNA are the basis for many potential biomedical applications of copper complexes, ranging from DNA structural probes and foot printing agents to anticancer drugs to gene delivery. Ideally, a complex binds selectively to a specific DNA sequence, conformation or higher order structure or causes a permanent structural transition or conformational change. The literature in this field has been constantly growing over the past two to three decades as new applications were emerging. This gives an overview of the state-of-the-art of DNA-binding Cu complexes designed for applications in bioinorg. and medicinal inorg. chem., with a focus on the most relevant ligand classes, i.e. amino acids and peptides, phenanthrolines and phenanthroline-like ligands, terpyridines, porphyrins, Schiff bases and (thio)semicarbazones, polyaza macrocycles and tripodal ligands.
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    26. 26
      Krasnovskaya, O.; Naumov, A.; Guk, D.; Gorelkin, P.; Erofeev, A.; Beloglazkina, E.; Majouga, A. Copper Coordination Compounds as Biologically Active Agents. Int. J. Mol. Sci. 2020, 21, 3965,  DOI: 10.3390/ijms21113965
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      Copper coordination compounds as biologically active agents
      Krasnovskaya, Olga; Naumov, Alexey; Guk, Dmitry; Gorelkin, Peter; Erofeev, Alexander; Beloglazkina, Elena; Majouga, Alexander
      International Journal of Molecular Sciences (2020), 21 (11), 3965CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)
      Copper-contg. coordination compds. attract wide attention due to the redox activity and biogenicity of copper ions, providing multiple pathways of biol. activity. The pharmacol. properties of metal complexes can be fine-tuned by varying the nature of the ligand and donor atoms. Copper-contg. coordination compds. are effective antitumor agents, constituting a less expensive and safer alternative to classical platinum-contg. chemotherapy, and are also effective as antimicrobial, antituberculosis, antimalarial, antifugal, and anti-inflammatory drugs. 64Cu-labeled coordination compds. are promising PET imaging agents for diagnosing malignant pathologies, including head and neck cancer, as well as the hallmark of Alzheimer's disease amyloid-β (Aβ). In this review article, we summarize different strategies for possible use of coordination compds. in the treatment and diagnosis of various diseases, and also various studies of the mechanisms of antitumor and antimicrobial action.
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    27. 27
      Kellett, A.; Molphy, Z.; McKee, V.; Slator, C. In Metal-based Anticancer Agents; Casini, A., Vessières, A., Meier-Menches, S. M., Eds.; The Royal Society of Chemistry, 2019; pp 91– 119.
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      Shao, S.; Si, J.; Shen, Y. Copper as the Target for Anticancer Nanomedicine. Adv. Ther. 2019, 2, 1800147,  DOI: 10.1002/adtp.201800147
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      There is no corresponding record for this reference.
    29. 29
      Balsano, C.; Porcu, C.; Sideri, S. Is copper a new target to counteract the progression of chronic diseases?. Metallomics 2018, 10, 1712– 1722,  DOI: 10.1039/c8mt00219c
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      Is copper a new target to counteract the progression of chronic diseases?
      Balsano, Clara; Porcu, Cristiana; Sideri, Silvia
      Metallomics (2018), 10 (12), 1712-1722CODEN: METAJS; ISSN:1756-591X. (Royal Society of Chemistry)
      A review. Altered regulation of copper (Cu) homeostasis may contribute to the development of many pathologies, such as metabolic, cardiovascular, neurodegenerative and cancerous diseases. Cu serum concns. are strictly related to oxidative stress. During the past decade, it has been well demonstrated that even marginal deficits of this element contribute to development and progression of a no. of chronic diseases. On the other hand, an excess of Cu may become a potent oxidant causing the generation of reactive oxygen species (ROS) and leading to the formation of macromols. dangerous to health. In this review we will describe several chronic inflammatory diseases pathogenically related to the alteration of serum copper levels. Some considerations on present and future perspectives for use of natural antioxidants as effective drugs for the treatment of chronic diseases will be made to shed a glimmer of light on some of the mechanisms employed by natural antioxidants in controlling the distribution and concn. of biometals.
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    30. 30
      Denoyer, D.; Masaldan, S.; La Fontaine, S.; Cater, M. A. Targeting copper in cancer therapy: “Copper That Cancer”. Metallomics 2015, 7, 1459– 1476,  DOI: 10.1039/C5MT00149H
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      Targeting copper in cancer therapy: 'Copper That Cancer'
      Denoyer, Delphine; Masaldan, Shashank; La Fontaine, Sharon; Cater, Michael A.
      Metallomics (2015), 7 (11), 1459-1476CODEN: METAJS; ISSN:1756-591X. (Royal Society of Chemistry)
      Copper is an essential micronutrient involved in fundamental life processes that are conserved throughout all forms of life. The ability of copper to catalyze oxidn.-redn. (redox) reactions, which can inadvertently lead to the prodn. of reactive oxygen species (ROS), necessitates the tight homeostatic regulation of copper within the body. Many cancer types exhibit increased intratumoral copper and/or altered systemic copper distribution. The realization that copper serves as a limiting factor for multiple aspects of tumor progression, including growth, angiogenesis and metastasis, has prompted the development of copper-specific chelators as therapies to inhibit these processes. Another therapeutic approach utilizes specific ionophores that deliver copper to cells to increase intracellular copper levels. The therapeutic window between normal and cancerous cells when intracellular copper is forcibly increased, is the premise for the development of copper-ionophores endowed with anticancer properties. Also under investigation is the use of copper to replace platinum in coordination complexes currently used as mainstream chemotherapies. In comparison to platinum-based drugs, these promising copper coordination complexes may be more potent anticancer agents, with reduced toxicity toward normal cells and they may potentially circumvent the chemoresistance assocd. with recurrent platinum treatment. In addn., cancerous cells can adapt their copper homeostatic mechanisms to acquire resistance to conventional platinum-based drugs and certain copper coordination complexes can re-sensitize cancer cells to these drugs. This review will outline the biol. importance of copper and copper homeostasis in mammalian cells, followed by a discussion of our current understanding of copper dysregulation in cancer, and the recent therapeutic advances using copper coordination complexes as anticancer agents.
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    31. 31
      Gandin, V.; Trenti, A.; Porchia, M.; Tisato, F.; Giorgetti, M.; Zanusso, I.; Trevisi, L.; Marzano, C. Homoleptic phosphino copper(i) complexes with in vitro and in vivo dual cytotoxic and anti-angiogenic activity. Metallomics 2015, 7, 1497– 1507,  DOI: 10.1039/C5MT00163C
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      Homoleptic phosphino copper(I) complexes with in vitro and in vivo dual cytotoxic and anti-angiogenic activity
      Gandin, V.; Trenti, A.; Porchia, M.; Tisato, F.; Giorgetti, M.; Zanusso, I.; Trevisi, L.; Marzano, C.
      Metallomics (2015), 7 (11), 1497-1507CODEN: METAJS; ISSN:1756-591X. (Royal Society of Chemistry)
      Homoleptic, tetrahedral Cu(I) complexes of the type [Cu(P)4]BF4 (1-3), where P are the phosphine ligands, 1,3,5-triaza-7-phosphaadamantane (PTA), 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (DAPTA) and 2-thia-1,3,5-triaza-phosphoaadamantane-2,2-dioxide (PTA-SO2), have been prepd. Novel complexes [Cu(DAPTA)4]BF42 and [Cu(PTA-SO2)4]BF43 have been fully characterized by means of spectroscopic methods, corroborated by XAS-EXAFS anal. of 2. In vitro cell culture expts. revealed a significant antiproliferative activity for Cu(I) compds. against several human cancer cell lines derived from solid tumors with preferential cell growth inhibition towards tumor compared to non-malignant cells. In vitro monitoring of migration and capillary-like tube formation of human umbilical vein endothelial cells (HUVECs) showed an anti-angiogenic effect of copper(I) complexes at sub-cytotoxic concns. In vivo studies on the antitumor efficacy and ability to inhibit angiogenesis confirmed the dual cytotoxic and anti-angiogenic properties of Cu(I) derivs.
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    32. 32
      Silva-Platas, C.; Guerrero-Beltrán, C. E.; Carrancá, M.; Castillo, E. C.; Bernal-Ramírez, J.; Oropeza-Almazán, Y.; González, L. N.; Rojo, R.; Martínez, L. E.; Valiente-Banuet, J.; Ruiz-Azuara, L.; Bravo-Gómez, M. E.; García, N.; Carvajal, K.; García-Rivas, G. Antineoplastic copper coordinated complexes (Casiopeinas) uncouple oxidative phosphorylation and induce mitochondrial permeability transition in cardiac mitochondria and cardiomyocytes. J. Bioenerg. Biomembr. 2016, 48, 43– 54,  DOI: 10.1007/s10863-015-9640-x
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      Antineoplastic copper coordinated complexes (Casiopeinas) uncouple oxidative phosphorylation and induce mitochondrial permeability transition in cardiac mitochondria and cardiomyocytes
      Silva-Platas, Christian; Guerrero-Beltran, Carlos Enrique; Carranca, Mariana; Castillo, Elena Cristina; Bernal-Ramirez, Judith; Oropeza-Almazan, Yuriana; Gonzalez, Lorena N.; Rojo, Rocio; Martinez, Luis Enrique; Valiente-Banuet, Juan; Ruiz-Azuara, Lena; Bravo-Gomez, Maria Elena; Garcia, Noemi; Carvajal, Karla; Garcia-Rivas, Gerardo
      Journal of Bioenergetics and Biomembranes (2016), 48 (1), 43-54CODEN: JBBID4; ISSN:0145-479X. (Springer)
      Copper-based drugs, Casiopeinas (Cas), exhibit antiproliferative and antineoplastic activities in vitro and in vivo, resp. Unfortunately, the clin. use of these novel chemotherapeutics could be limited by the development of dose-dependent cardiotoxicity. In addn., the mol. mechanisms underlying Cas cardiotoxicity and anticancer activity are not completely understood. Here, we explore the potential impact of Cas on the cardiac mitochondria energetics as the mol. mechanisms underlying Cas-induced cardiotoxicity. To explore the properties on mitochondrial metab., we detd. Cas effects on respiration, membrane potential, membrane permeability, and redox state in isolated cardiac mitochondria. The effect of Cas on the mitochondrial membrane potential (Δψm) was also evaluated in isolated cardiomyocytes by confocal microscopy and flow cytometry. Cas IIIEa, IIgly, and IIIia predominately inhibited maximal NADH- and succinate-linked mitochondrial respiration, increased the state-4 respiration rate and reduced membrane potential, suggesting that Cas also act as mitochondrial uncouplers. Interestingly, cyclosporine A inhibited Cas-induced mitochondrial depolarization, suggesting the involvement of mitochondrial permeability transition pore (mPTP). Similarly to isolated mitochondria, in isolated cardiomyocytes, Cas treatment decreased the Δψm and cyclosporine A treatment prevented mitochondrial depolarization. The prodn. of H2O2 increased in Cas-treated mitochondria, which might also increase the oxidn. of mitochondrial proteins such as adenine nucleotide translocase. In accordance, an antioxidant scavenger (Tiron) significantly diminished Cas IIIia mitochondrial depolarization. Cas induces a prominent loss of membrane potential, assocd. with alterations in redox state, which increases mPTP opening, potentially due to thiol-dependent modifications of the pore, suggesting that direct or indirect inhibition of mPTP opening might reduce Cas-induced cardiotoxicity.
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      Weekley, C. M.; He, C. Developing drugs targeting transition metal homeostasis. Curr. Opin. Chem. Biol. 2017, 37, 26– 32,  DOI: 10.1016/j.cbpa.2016.12.011
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      Developing drugs targeting transition metal homeostasis
      Weekley, Claire M.; He, Chuan
      Current Opinion in Chemical Biology (2017), 37 (), 26-32CODEN: COCBF4; ISSN:1367-5931. (Elsevier B.V.)
      Metal dyshomeostasis is involved in the pathogenesis and progression of diseases including cancer and neurodegenerative diseases. Metal chelators and ionophores are well known modulators of transition metal homeostasis, and a no. of these mols. are in clin. trials. Metal-binding compds. are not the only drugs capable of targeting transition metal homeostasis. This review presents recent highlights in the development of chelators and ionophores for the treatment of cancer and neurodegenerative disease. Moreover, we discuss the development of small mols. that alter copper and iron homeostasis by inhibiting metal transport proteins. Finally, we consider the emergence of metal regulatory factor 1 as a drug target in diseases where it mediates zinc-induced signalling cascades leading to pathogenesis.
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      Wehbe, M.; Leung, A. W. Y.; Abrams, M. J.; Orvig, C.; Bally, M. B. A Perspective─can copper complexes be developed as a novel class of therapeutics?. Dalton Trans. 2017, 46, 10758– 10773,  DOI: 10.1039/C7DT01955F
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      A Perspective - can copper complexes be developed as a novel class of therapeutics?
      Wehbe, Mohamed; Leung, Ada W. Y.; Abrams, Michael J.; Orvig, Chris; Bally, Marcel B.
      Dalton Transactions (2017), 46 (33), 10758-10773CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
      Although copper-ligand complexes appear to be promising as a new class of therapeutics, other than the family of copper(II) coordination compds. referred to as casiope´inas these compds. have yet to reach the clinic for human use. The pharmaceutical challenges assocd. with developing copper-based therapeutics will be presented in this article along with a discussion of the potential for high-throughput chem., computer-aided drug design, and nanotechnol. to address the development of this important class of drug candidates.
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      Baldari, S.; Di Rocco, G.; Toietta, G. Current Biomedical Use of Copper Chelation Therapy. Int. J. Mol. Sci. 2020, 21, 1069,  DOI: 10.3390/ijms21031069
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      Current biomedical use of copper chelation therapy
      Baldari, Silvia; Rocco, Giuliana Di; Toietta, Gabriele
      International Journal of Molecular Sciences (2020), 21 (3), 1069CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)
      A review. Copper is an essential microelement that plays an important role in a wide variety of biol. processes. Copper concn. has to be finely regulated, as any imbalance in its homeostasis can induce abnormalities. In particular, excess copper plays an important role in the etiopathogenesis of the genetic disease Wilson's syndrome, in neurol. and neurodegenerative pathologies such as Alzheimer's and Parkinson's diseases, in idiopathic pulmonary fibrosis, in diabetes, and in several forms of cancer. Copper chelating agents are among the most promising tools to keep copper concn. at physiol. levels. In this review, we focus on the most relevant compds. exptl. and clin. evaluated for their ability to counteract copper homeostasis deregulation. In particular, we provide a general overview of the main disorders characterized by a pathol. increase in copper levels, summarizing the principal copper chelating therapies adopted in clin. trials.
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      Santini, C.; Pellei, M.; Gandin, V.; Porchia, M.; Tisato, F.; Marzano, C. Advances in Copper Complexes as Anticancer Agents. Chem. Rev. 2014, 114, 815– 862,  DOI: 10.1021/Cr400135x
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      Advances in Copper Complexes as Anticancer Agents
      Santini, Carlo; Pellei, Maura; Gandin, Valentina; Porchia, Marina; Tisato, Francesco; Marzano, Cristina
      Chemical Reviews (Washington, DC, United States) (2014), 114 (1), 815-862CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      This review describes advances in the synthesis, design, and development of copper complexes as anticancer agents in the last 4 years. Interest in this field has rapidly grown in recent years, as illustrated by the increasing no. of publications reported since 2000. This summary covers the period 2008-2012 and follows the authors' previous efforts in the same area. Furthermore, the authors summarize recent findings on (i) identification of the main mol. targets and cellular pathways involved in the copper complexes-induced antiproliferative effects and (ii) the state of art of in vivo studies on the antitumor activity of copper compds. This overview would like to be a useful tool for the research community actively involved in the copper-based anticancer drug discovery.
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      Lelièvre, P.; Sancey, L.; Coll, J.-L.; Deniaud, A.; Busser, B. The Multifaceted Roles of Copper in Cancer: A Trace Metal Element with Dysregulated Metabolism, but Also a Target or a Bullet for Therapy. Cancers 2020, 12, 3594,  DOI: 10.3390/cancers12123594
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      The multifaceted roles of copper in cancer: a trace metal element with dysregulated metabolism, but also a target or a bullet for therapy
      Lelievre, Pierre; Sancey, Lucie; Coll, Jean-Luc; Deniaud, Aurelien; Busser, Benoit
      Cancers (2020), 12 (12), 3594CODEN: CANCCT; ISSN:2072-6694. (MDPI AG)
      In the human body, copper (Cu) is a major and essential player in a large no. of cellular mechanisms and signaling pathways. The involvement of Cu in oxidn.-redn. reactions requires close regulation of copper metab. in order to avoid toxic effects. In many types of cancer, variations in copper protein levels have been demonstrated. These variations result in increased concns. of intratumoral Cu and alterations in the systemic distribution of copper. Such alterations in Cu homeostasis may promote tumor growth or invasiveness or may even confer resistance to treatments. Once characterized, the dysregulated Cu metab. is pinpointing several promising biomarkers for clin. use with prognostic or predictive capabilities. The altered Cu metab. in cancer cells and the different responses of tumor cells to Cu are strongly supporting the development of treatments to disrupt, deplete, or increase Cu levels in tumors. The metallic nature of Cu as a chem. element is key for the development of anticancer agents via the synthesis of nanoparticles or copper-based complexes with antineoplastic properties for therapy. Finally, some of these new therapeutic strategies such as chelators or ionophores have shown promising results in a preclin. setting, and others are already in the clinic.
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      Medici, S.; Peana, M.; Nurchi, V. M.; Lachowicz, J. I.; Crisponi, G.; Zoroddu, M. A. Noble metals in medicine: Latest advances. Coord. Chem. Rev. 2015, 284, 329– 350,  DOI: 10.1016/j.ccr.2014.08.002
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      Noble metals in medicine: Latest advances
      Medici, Serenella; Peana, Massimiliano; Nurchi, Valeria Marina; Lachowicz, Joanna I.; Crisponi, Guido; Zoroddu, Maria Antonietta
      Coordination Chemistry Reviews (2015), 284 (), 329-350CODEN: CCHRAM; ISSN:0010-8545. (Elsevier B.V.)
      A review. History shows that metal-based drugs and remedies have been known and used since very ancient times. For example, silver was employed in the treatment of wounds and ulcers according to the Greek physician Hippocrates, but its antimicrobial properties had probably been recognized long before because it was used to make vessels for storing liqs. in pure form. The ancient Egyptians also knew how to sterilize water with copper. The medical use of gold can be dated back to 2500 B.C. in China. However, the new era of metal-based medicine started almost 50 years ago when cisplatin was shown to inhibit cellular division in Escherichia coli, thereby leading to the first studies of its antitumor activity in rats and its assessment as one of the most powerful drugs for use against different types of cancer, although many other novel metal-based drugs are promising and they are attracting growing attention in modern clin. medicine. Gold salts and arsenic compds. have been in use for decades in the treatment of rheumatoid arthritis and syphilis, resp., but studies of cisplatin have definitely shifted the attention of researchers to the pool of transition "heavy" metals as potential therapeutic agents. Rhodium, iridium, palladium, osmium, and the other so-called noble elements have been the subjects of intensive investigations, thereby leading to the prodn. of a series of complex compds. with remarkable anticancer activities, as well as antirheumatic, antimalarial, and antimicrobial drugs. The no. of published studies in this field is huge and they have already been the subjects of careful review. In this review, we provide a detailed account of the latest results (2010-2013) and their potential uses in the cure of severe diseases.
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      Tisato, F.; Marzano, C.; Porchia, M.; Pellei, M.; Santini, C. Copper in Diseases and Treatments, and Copper-Based Anticancer Strategies. Med. Res. Rev. 2010, 30, 708– 749,  DOI: 10.1002/Med.20174
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      Copper in diseases and treatments, and copper-based anticancer strategies
      Tisato, Francesco; Marzano, Cristina; Porchia, Marina; Pellei, Maura; Santini, Carlo
      Medicinal Research Reviews (2010), 30 (4), 708-749CODEN: MRREDD; ISSN:0198-6325. (John Wiley & Sons, Inc.)
      A review. Copper is found in all living organisms and is a crucial trace element in redox chem., growth and development. It is important for the function of several enzymes and proteins involved in energy metab., respiration, and DNA synthesis, notably cytochrome oxidase, superoxide dismutase, ascorbate oxidase, and tyrosinase. The major functions of copper-biol. mols. involve oxidn.-redn. reactions in which they react directly with mol. oxygen to produce free radicals. Therefore, copper requires tightly regulated homeostatic mechanisms to ensure adequate supplies without any toxic effects. Overload or deficiency of copper is assocd., resp., with Wilson disease (WD) and Menkes disease (MD), which are of genetic origin. Researches on Menkes and Wilson disorders have provided useful insights in the field of copper homeostasis and in particular into the understanding of intracellular trafficking and distribution of copper at mol. levels. Therapies based on metal supplementation with copper histidine or removal of copper excess by means of specific copper chelators are currently effective in treating MD and WD, resp. Copper chelation therapy is now attracting much attention for the investigation and treatment of various neurodegenerative disorders such as Alzheimer, Parkinson and CreutzfeldtJakob. An excess of copper appears to be an essential co-factor for angiogenesis. Moreover, elevated levels of copper have been found in many types of human cancers, including prostate, breast, colon, lung, and brain. On these basis, the employment of copper chelators has been reported to be of therapeutic value in the treatment of several types of cancers as anti-angiogenic mols. More recently, mixts. of copper chelators with copper salts have been found to act as efficient proteasome inhibitors and apoptosis inducers, specifically in cancer cells. Moreover, following the worldwide success of platinum(II) compds. in cancer chemotherapy, several families of individual copper complexes have been studied as potential antitumor agents. These investigations, revealing the occurrence of mechanisms of action quite different from platinum drugs, head toward the development of new anticancer metallodrugs with improved specificity and decreased toxic side effects.
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      Marzano, C.; Pellei, M.; Tisato, F.; Santini, C. Copper complexes as anticancer agents. Anti-Cancer Agents Med. Chem. 2009, 9, 185– 211,  DOI: 10.2174/187152009787313837
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      Copper complexes as anticancer agents
      Marzano, Cristina; Pellei, Maura; Tisato, Francesco; Santini, Carlo
      Anti-Cancer Agents in Medicinal Chemistry (2009), 9 (2), 185-211CODEN: AAMCE4; ISSN:1871-5206. (Bentham Science Publishers Ltd.)
      A review. Metal-based antitumor drugs play a relevant role in antiblastic chemotherapy. Cisplatin is regarded as one of the most effective drugs, even if severe toxicities and drug resistance phenomena limit its clin. use. Therefore, in recent years there has been a rapid expansion in research and development of novel metal-based anticancer drugs to improve clin. effectiveness, to reduce general toxicity and to broaden the spectrum of activity. The variety of metal ion functions in biol. has stimulated the development of new metallo drugs other than Pt drugs with the aim to obtain compds. acting via alternative mechanisms of action. Among non-Pt compds., copper complexes are potentially attractive as anticancer agents. Actually, since many years a lot of researches have actively investigated copper compds. based on the assumption proposal that endogenous metals may be less toxic. It has been established that the properties of copper-coordinated compds. are largely detd. by the nature of ligands and donor atoms bound to the metal ion. In this review, the most remarkable achievements in the design and development of copper(I, II) complexes as antitumor agents are discussed. Special emphasis has been focused on the identification of structure-activity relationships for the different classes of copper(I,II) complexes. This work was motivated by the observation that no comprehensive surveys of copper complexes as anticancer agents were available in the literature. Moreover, up to now, despite the enormous efforts in synthesizing different classes of copper complexes, very few data concerning the mol. basis of the mechanisms underlying their antitumor activity are available. This overview, collecting the most significant strategies adopted in the last ten years to design promising anticancer copper(I,II) compds., would be a help to the researchers working in this field.
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      Zehra, S.; Tabassum, S.; Arjmand, F. Biochemical pathways of copper complexes: progress over the past 5 years. Drug Discovery Today 2021, 26, 1086– 1096,  DOI: 10.1016/j.drudis.2021.01.015
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      Biochemical pathways of copper complexes: progress over the past 5 years
      Zehra, Siffeen; Tabassum, Sartaj; Arjmand, Farukh
      Drug Discovery Today (2021), 26 (4), 1086-1096CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)
      A review. Copper is an essential trace element with vital roles in many metalloenzymes; it is also prominent among nonplatinum anticancer metallodrugs. Copper-based complexes are endogenously biocompatible, tenfold more potent than cisplatin, exhibit fewer adverse effects, and have a wide therapeutic window. In cancer biol., copper acts as an antitumor agent by inhibiting cancer via multiple pathways. Herein, we present an overview of advances in copper complexes as 'lead' antitumor drug candidates, and in understanding their biochem. and pharmacol. pathways over the past 5 years. This review will help to develop more efficacious therapeutics to improve clin. outcomes for cancer treatments.
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      Singh, N. K.; Kumbhar, A. A.; Pokharel, Y. R.; Yadav, P. N. Anticancer potency of copper(II) complexes of thiosemicarbazones. J. Inorg. Biochem. 2020, 210, 111134,  DOI: 10.1016/j.jinorgbio.2020.111134
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      Anticancer potency of copper(II) complexes of thiosemicarbazones
      Singh, Narendra Kumar; Kumbhar, Anupa A.; Pokharel, Yuba Raj; Yadav, Paras Nath
      Journal of Inorganic Biochemistry (2020), 210 (), 111134CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier Inc.)
      A review. Being a structural and catalytic cofactor in a no. of biol. pathways, copper accumulates in tumors owing to selective permeability of the cancer cell membranes. Copper(II) ion forms the active centers in a large no. of metalloproteins. The coordination of Schiff's base ligands to the metal ion results in the high extent of increase in anticancer activity. The copper(II) complexes can cleave DNA through oxidative and hydrolytic pathways, cell apoptosis via intrinsic reactive oxygen species (ROS) mediated mitochondrial pathway due to excessive prodn. of ROS and hence, are found more active than Ni and Pt complexes. Flexible Cu(I/II) redox behavior helps the copper complexes to form more potent, clin. effective and less toxic copper based antiproliferative drugs of lower IC50 value and higher growth inhibitory activity. Copper(II) complexes of thiosemicarbazones of Isatin, Pyridine, Benzoyl pyridine, Diacetyl/Dimethyl glyoxal, Acetophenone/Acetoacetanalide, Thiazole/Pyrazole, Quinoline, Carboxybenzaldehyde, Cinnamaldehyde/Cuminaldehyde, Citronellal, Chromone, Pyridoxal, 8-Ethyl-2-hydroxytricyclo (7.3.1.02,7) tridecan-13-one, Acyl Diazines, Naphthalene, Proline, 5-Formyluracil, 2-Hydroxy-8-propyltricyclo (7.3.1.02,7) tridecan-13-one, 9-cis-Retinal, Curcumin, Helicin (Salicylaldehyde-β-D-glucoside), Thiophene carboxaldehyde, Salicylaldehyde, Iminodiacetate, and 3-Formyl-4-hydroxy benzenesulfonic acid have been found to exhibit more anticancer activity toward HCT116, MCF7, A549, U937, HeLa, HepG2, SGC-7901, A2780 cell lines than that of their corresponding thiosemicarbazones and std. topoisomerase-II inhibitors.
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      Allardyce, C. S.; Dyson, P. J. Metal-based drugs that break the rules. Dalton Trans. 2016, 45, 3201– 3209,  DOI: 10.1039/C5DT03919C
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      Metal-based drugs that break the rules
      Allardyce, Claire S.; Dyson, Paul J.
      Dalton Transactions (2016), 45 (8), 3201-3209CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
      Cisplatin and other platinum compds. have had a huge impact in the treatment of cancers and are applied in the majority of anticancer chemotherapeutic regimens. The success of these compds. has biased the approaches used to discover new metal-based anticancer drugs. In this perspective we highlight compds. that are apparently incompatible with the more classical (platinum-derived) concepts employed in the development of metal-based anticancer drugs, with respect to both compd. design and the approaches used to validate their utility. Possible design approaches for the future are also suggested.
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      Spreckelmeyer, S.; Orvig, C.; Casini, A. Cellular Transport Mechanisms of Cytotoxic Metallodrugs: An Overview beyond Cisplatin. Molecules 2014, 19, 15584– 15610,  DOI: 10.3390/molecules191015584
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      Cellular transport mechanisms of cytotoxic metallodrugs: an overview beyond cisplatin
      Spreckelmeyer, Sarah; Orvig, Chris; Casini, Angela
      Molecules (2014), 19 (10), 15584-15610, 27 pp.CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
      A review. The field of medicinal inorg. chem. has grown consistently during the past 50 years; however, metal-contg. coordination compds. represent only a minor proportion of drugs currently on the market, indicating that research in this area has not yet been thoroughly realized. Although platinum-based drugs as cancer chemotherapeutic agents have been widely studied, exact knowledge of the mechanisms governing their accumulation in cells is still lacking. However, evidence suggests active uptake and efflux mechanisms are involved; this may be involved also in other exptl. metal coordination and organometallic compds. with promising antitumor activities in vitro and in vivo, such as ruthenium and gold compds. Such knowledge would be necessary to elucidate the balance between activity and toxicity profiles of metal compds. In this review, we present an overview of the information available on the cellular accumulation of Pt compds. from in vitro, in vivo and clin. studies, as well as a summary of reports on the possible accumulation mechanisms for different families of exptl. anticancer metal complexes (e.g., Ru Au and Ir). Finally, we discuss the need for rationalization of the investigational approaches available to study metallodrug cellular transport.
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      Zaki, M.; Arjmand, F.; Tabassum, S. Current and future potential of metallo drugs: Revisiting DNA-binding of metal containing molecules and their diverse mechanism of action. Inorg. Chim. Acta 2016, 444, 1– 22,  DOI: 10.1016/j.ica.2016.01.006
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      Current and future potential of metallo drugs: Revisiting DNA-binding of metal containing molecules and their diverse mechanism of action
      Zaki, Mehvash; Arjmand, Farukh; Tabassum, Sartaj
      Inorganica Chimica Acta (2016), 444 (), 1-22CODEN: ICHAA3; ISSN:0020-1693. (Elsevier B.V.)
      A review. Cancer treatments regimes which include conventional chemotherapy have not proved so successful in curing human malignancies. Failures to these treatment modalities include inherent resistance, systemic toxicity and severe side effects. Out of 50% patients administrated to chemotherapy, only 5% undergoes survival. Therefore, identification of new drug design and therapeutic strategies that could target cancer cells leaving normal cells unaffected still continues to be a challenge. Despite advances that have led to the development of new therapies, treatment options are still limited for many types of human cancers particularly with those undifferentiated phenotypes. This review provides an overview of metal based anticancer drugs in clin. trials and the serious side effects caused by these drugs led the chemists to search for the new diagnostic and therapeutic agents. In particular, the authors focus on metal complexes of copper, zinc, silver and gold complexes with an emphasis on the new strategies used in the development of new antitumor agents.
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      Molinaro, C.; Martoriati, A.; Pelinski, L.; Cailliau, K. Copper Complexes as Anticancer Agents Targeting Topoisomerases I and II. Cancers 2020, 12, 2863,  DOI: 10.3390/cancers12102863
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      Copper complexes as anticancer agents targeting topoisomerases I and II
      Molinaro, Caroline; Martoriati, Alain; Pelinski, Lydie; Cailliau, Katia
      Cancers (2020), 12 (10), 2863CODEN: CANCCT; ISSN:2072-6694. (MDPI AG)
      Organometallics, such as copper compds., are cancer chemotherapeutics used alone or in combination with other drugs. One small group of copper complexes exerts an effective inhibitory action on topoisomerases, which participate in the regulation of DNA topol. Copper complexes inhibitors of topoisomerases 1 and 2 work by different mol. mechanisms, analyzed herein. They allow genesis of DNA breaks after the formation of a ternary complex, or act in a catalytic mode, often display DNA intercalative properties and ROS prodn., and sometimes display dual effects. These amplified actions have repercussions on the cell cycle checkpoints and death effectors. Copper complexes of topoisomerase inhibitors are analyzed in a broader synthetic view and in the context of cancer cell mutations. Finally, new emerging treatment aspects are depicted to encourage the expansion of this family of highly active anticancer drugs and to expend their use in clin. trials and future cancer therapy.
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      Zanella, A.; Gandin, V.; Porchia, M.; Refosco, F.; Tisato, F.; Sorrentino, F.; Scutari, G.; Rigobello, M. P.; Marzano, C. Cytotoxicity in human cancer cells and mitochondrial dysfunction induced by a series of new copper(I) complexes containing tris(2-cyanoethyl)phosphines. Invest. New Drugs 2011, 29, 1213– 1223,  DOI: 10.1007/s10637-010-9466-7
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      Cytotoxicity in human cancer cells and mitochondrial dysfunction induced by a series of new copper(I) complexes containing tris(2-cyanoethyl)phosphines
      Zanella, Alessandro; Gandin, Valentina; Porchia, Marina; Refosco, Fiorenzo; Tisato, Francesco; Sorrentino, Francesca; Scutari, Guido; Rigobello, Maria Pia; Marzano, Cristina
      Investigational New Drugs (2011), 29 (6), 1213-1223CODEN: INNDDK; ISSN:0167-6997. (Springer)
      Over the last few years a lot of research has been done to develop novel metal-based anti-cancer drugs, with the aim of improving clin. effectiveness, reducing general toxicity, and broadening the spectrum of activity. The search for novel metal-based antitumor drugs other than Pt agents includes the investigation of the cytotoxic activity of copper(I/II) compds. Among these copper agents, particular attention has been recently devoted to hydrophilic copper(I) species bearing phosphines because of their noteworthy stability in aq. media together with their remarkable in vitro cytotoxic activity. In this study we report on the synthesis, characterization and cytotoxic assays of a series of Cu(I) complexes with tris(2-cyanoethyl)phosphine (PCN) and bis(2-cyanoethyl)phenylphosphine (PCNPh). They were prepd. by reaction of [Cu(CH3CN)4]+ or CuX2 precursors with the pertinent phosphine in acetone or acetonitrile solns. producing compds. of the following formulation: [Cu(PCN)2]+ 2, [Cu(CH3CN)(PCN)]+ 3, [Cu(X)(PCN)] (X = Cl, 4; Br, 5), and [Cu(PCNPh)2]+ 6. The new copper(I) complexes were tested for their cytotoxic properties against a panel of several human tumor cell lines. Cellular copper uptake rate was correlated with cell growth inhibition in 2008 human ovarian cancer cells. Moreover, copper(I)-PCN complexes were evaluated for their ability to alter the most relevant mitochondrial pathophysiol. parameters such as respiration, coupling, ATP-synthetase activity and membrane potential in isolated mitochondria. These data were correlated with changes in mitochondrial membrane potential and prodn. of reactive oxygen species (ROS) in drug-treated 2008 cells.
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      Otero, A.; Fernández-Baeza, J.; Lara-Sánchez, A.; Sánchez-Barba, L. F. Metal complexes with heteroscorpionate ligands based on the bis(pyrazol-1-yl)methane moiety: Catalytic chemistry. Coord. Chem. Rev. 2013, 257, 1806– 1868,  DOI: 10.1016/j.ccr.2013.01.027
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      Metal complexes with heteroscorpionate ligands based on the bis(pyrazol-1-yl)methane moiety: Catalytic chemistry
      Otero, Antonio; Fernandez-Baeza, Juan; Lara-Sanchez, Agustin; Sanchez-Barba, Luis F.
      Coordination Chemistry Reviews (2013), 257 (11-12), 1806-1868CODEN: CCHRAM; ISSN:0010-8545. (Elsevier B.V.)
      A review. This review covers studies related to the design of ligands, synthetic pathways and catalytic processes of some families of metal complexes that contain heteroscorpionate ligands based on bis(pyrazol-1-yl)methane moieties.
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    49. 49
      Pellei, M.; Papini, G.; Trasatti, A.; Giorgetti, M.; Tonelli, D.; Minicucci, M.; Marzano, C.; Gandin, V.; Aquilanti, G.; Dolmella, A.; Santini, C. Nitroimidazole and glucosamine conjugated heteroscorpionate ligands and related copper(II) complexes. Syntheses, biological activity and XAS studies. Dalton Trans. 2011, 40, 9877– 9888,  DOI: 10.1039/c1dt10486a
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      Nitroimidazole and glucosamine conjugated heteroscorpionate ligands and related copper(II) complexes. Syntheses, biological activity and XAS studies
      Pellei, Maura; Papini, Grazia; Trasatti, Andrea; Giorgetti, Marco; Tonelli, Domenica; Minicucci, Marco; Marzano, Cristina; Gandin, Valentina; Aquilanti, Giuliana; Dolmella, Alessandro; Santini, Carlo
      Dalton Transactions (2011), 40 (38), 9877-9888CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
      New nitroimidazole and glucosamine conjugated heteroscorpionate ligands, 2,2-bis(3,5-dimethyl-1H-pyrazol-1-yl)-N-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)acetamide (LMN) and 1,3,4,6-tetra-O-acetyl-2-{[bis(3,5-dimethyl-1H-pyrazol-1-yl)acetyl]amino}-2-deoxy-β-d-glucopyranose (LDAC), resp., were synthesized by direct coupling of preformed side chain acid and amine components. The related Cu(II) complexes {[(LMN)2Cu]Cl2}, and {[(LDAC)2Cu]Cl2} were prepd. from the reaction of CuCl2.2H2O with LMN or LDAC ligand in MeOH soln. Single crystal structural characterization was undertaken for the LMN ligand. In the absence of a coordinated metal core, the overall arrangement of the ligand was detd. by some loose intra- and inter-mol. nonbonding contacts. X-ray Absorption Spectroscopy (XAS) was used to probe the local structure of the two Cu(II) complexes, {[(LMN)2Cu]Cl2} and {[(LDAC)2Cu]Cl2}. The EXAFS anal. has permitted the identification of the local environment of the Cu site. Cu interacts with 2 units of ligand in both complexes, and it is 6-fold coordinated. Its local structure is described by four Cu-N and two Cu-O interactions to form a pseudo-octahedron core, with a 0.14 Å lengthening of the Cu-O bond length in the case of LDAC complex with respect to the LMN one, likely due to the higher steric hindrance of the glucosamine moiety. The XANES anal. agrees with these results, also confirming the Cu(II) formal Cu oxidn. state for both complexes. The new Cu(II) complexes {[(LMN)2Cu]Cl2} and {[(LDAC)2Cu]Cl2} as well as the corresponding uncoordinated ligands were evaluated for their cytotoxic activity towards a panel of several human tumor cell lines. Both Cu(II) complexes show similar spectra of cytotoxicity and very low resistance factors (RF < 2) against C13* ovarian cancer cells which have acquired resistance to cisplatin.
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      Giorgetti, M.; Tonelli, S.; Zanelli, A.; Aquilanti, G.; Pellei, M.; Santini, C. Synchrotron radiation X-ray absorption spectroscopic studies in solution and electrochemistry of a nitroimidazole conjugated heteroscorpionate copper(II) complex. Polyhedron 2012, 48, 174– 180,  DOI: 10.1016/j.poly.2012.08.073
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      Synchrotron radiation X-ray absorption spectroscopic studies in solution and electrochemistry of a nitroimidazole conjugated heteroscorpionate copper(II) complex
      Giorgetti, Marco; Tonelli, Silvia; Zanelli, Alberto; Aquilanti, Giuliana; Pellei, Maura; Santini, Carlo
      Polyhedron (2012), 48 (1), 174-180CODEN: PLYHDE; ISSN:0277-5387. (Elsevier Ltd.)
      Synchrotron radiation x-ray absorption spectroscopy was used to det. the soln. structure of the nitroimidazole conjugated heteroscorpionate Cu(II) complex {[(LMN)2Cu]Cl2} (LMN = 2,2-bis(3,5-dimethyl-1H-pyrazol-1-yl)-N-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)acetamide) at three different pH values. The strategy used for the XAS data anal. for a straightforward data interpretation is presented. The Cu center is coordinated by two mols. of ligands, describing a quasi-octahedral figure, in all studied solns., demonstrating the stability of the complex in soln. The Cu complex displays a pH dependence where the Cu-O first shell distance (from the carbonyl) lengthens at acid pH; the Cu-N equatorial distances are almost the same. XANES spectroscopy also indicates structural rearrangements occurring in soln. at various pH, where the spectrum at pH 4.4 displays the largest differences from the other ones. The cyclic voltammetry curves obtained on the same solns. show an irreversible peak due to the redn. of Cu(II) → Cu(I), which falls at potential of ∼0.4-0.5 V vs. SCE, and it is depending on pH. The potentiality of the joint XAS and electrochem. approach in the detn. of the structural characteristics of the solns. is highlighted.
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      Morelli, M. B.; Amantini, C.; Santoni, G.; Pellei, M.; Santini, C.; Cimarelli, C.; Marcantoni, E.; Petrini, M.; Del Bello, F.; Giorgioni, G.; Piergentili, A.; Quaglia, W. Novel antitumor copper(ii) complexes designed to act through synergistic mechanisms of action, due to the presence of an NMDA receptor ligand and copper in the same chemical entity. New J. Chem. 2018, 42, 11878– 11887,  DOI: 10.1039/c8nj01763h
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      Novel antitumor copper(II) complexes designed to act through synergistic mechanisms of action, due to the presence of an NMDA receptor ligand and copper in the same chemical entity
      Morelli, Maria Beatrice; Amantini, Consuelo; Santoni, Giorgio; Pellei, Maura; Santini, Carlo; Cimarelli, Cristina; Marcantoni, Enrico; Petrini, Marino; Del Bello, Fabio; Giorgioni, Gianfabio; Piergentili, Alessandro; Quaglia, Wilma
      New Journal of Chemistry (2018), 42 (14), 11878-11887CODEN: NJCHE5; ISSN:1144-0546. (Royal Society of Chemistry)
      In the present article the 1,4-dioxane deriv. 1, a potent noncompetitive NMDA receptor antagonist, showed cytotoxic activity in the MCF7 breast cancer cell line significantly higher than those of the functionally related compds. (S)-(+)-ketamine and MK-801. Encouraged by this result and considering that copper complexes have been highlighted to be promising anticancer agents, the NMDA receptor ligand 1 was linked to the bifunctionalizable species 2 and 3, affording the conjugated derivs. 4 and 5 that were used for the prepn. of the stable Cu(II) complexes 6 and 7. All the compds. were evaluated against a panel of human cancer cell lines derived from solid tumors. Complex 7 showed the best antitumor activity in all the studied cell lines. This result suggests that 7 might act through synergistic mechanisms of action due to the presence of the NMDA ligand 1 and copper(II) in the same chem. entity. Furthermore, the cellular mechanisms affected by complex 7 were assessed through cytofluorimetric and western blot analyses. Data suggested the induction of cell death through paraptosis mediated by endoplasmic reticulum (ER) stress.
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      Pellei, M.; Bagnarelli, L.; Luciani, L.; Del Bello, F.; Giorgioni, G.; Piergentili, A.; Quaglia, W.; De Franco, M.; Gandin, V.; Marzano, C.; Santini, C. Synthesis and Cytotoxic Activity Evaluation of New Cu(I) Complexes of Bis(pyrazol-1-yl) Acetate Ligands Functionalized with an NMDA Receptor Antagonist. Int. J. Mol. Sci. 2020, 21, 2616,  DOI: 10.3390/ijms21072616
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      Synthesis and cytotoxic activity evaluation of new Cu(I) complexes of bis(pyrazol-1-yl) acetate ligands functionalized with an NMDA receptor antagonist
      Pellei, Maura; Bagnarelli, Luca; Luciani, Lorenzo; Del Bello, Fabio; Giorgioni, Gianfabio; Piergentili, Alessandro; Quaglia, Wilma; De Franco, Michele; Gandin, Valentina; Marzano, Cristina; Santini, Carlo
      International Journal of Molecular Sciences (2020), 21 (7), 2616CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)
      In the present article, copper(I) complexes of bis(pyrazol-1-yl) carboxylic acid (LH), bis(3,5-dimethylpyrazol-1-yl) carboxylic acid (L2H), and bis(pyrazol-1-yl) acetates conjugated with an N-methyl-D-aspartate (NMDA) receptor antagonist (LNMDA or L2NMDA) and phosphane ligands (triphenylphosphine or 1,3,5-triaza-7-phosphaadamantane) were synthesized. The selection of an NMDA antagonist for the coupling with LH and L2H was suggested by the observation that NMDA receptors are expressed and play a role in different types of cancer models. All the new complexes showed a significant antitumor activity on a panel of human tumor cell lines of different histol., with cisplatin-sensitive, cisplatin-resistant, or multi-drug-resistant phenotype. Their half maximal inhibitory concn. (IC50) values were in the low- and sub-micromolar range and, in general, significantly lower than that of cisplatin. Interestingly, the fact that all the complexes proved to be significantly more active than cisplatin even in three-dimensional (3D) spheroids of H157 and BxPC3 cancer cells increased the relevance of the in vitro results. Finally, morphol. anal. revealed that the most representative complex 8 induced a massive swelling of the endoplasmic reticulum (ER) membrane, which is a clear sign of ER stress.
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      Schiesaro, I.; Venditti, I.; Pellei, M.; Santini, C.; Bagnarelli, L.; Iucci, G.; Battocchio, C.; Meneghini, C. Metal Coordination Core in Copper(II) Complexes Investigated by XAFS. Synchrotron Radiation Science and Applications; Springer Proceedings in Physics; Springer, 2021; Vol. 2021; pp 169– 179.
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      Beck, A.; Weibert, B.; Burzlaff, N. MonoanionicN,N,O-Scorpionate Ligands and their Iron(II) and Zinc(II) Complexes: Models for Mononuclear Active Sites of Non-Heme Iron Oxidases and Zinc Enzymes. Eur. J. Inorg. Chem. 2001, 2001, 521– 527,  DOI: 10.1002/1099-0682(200102)2001:2<521::aid-ejic521>3.0.co;2-q
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      Burzlaff, N.; Hegelmann, I.; Weibert, B. Bis(pyrazol-1-yl)acetates as tripodal “scorpionate” ligands in transition metal carbonyl chemistry: syntheses, structures and reactivity of manganese and rhenium carbonyl complexes of the type [LM(CO)3] (L = bpza, bdmpza). J. Organomet. Chem. 2001, 626, 16– 23,  DOI: 10.1016/s0022-328x(01)00648-9
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      Bis(pyrazol-1-yl)acetates as tripodal "scorpionate" ligands in transition metal carbonyl chemistry: syntheses, structures and reactivity of manganese and rhenium carbonyl complexes of the type [LM(CO)3] (L = bpza, bdmpza)
      Burzlaff, N.; Hegelmann, I.; Weibert, B.
      Journal of Organometallic Chemistry (2001), 626 (1-2), 16-23CODEN: JORCAI; ISSN:0022-328X. (Elsevier Science S.A.)
      The coordination of the ligands bis(3,5-dimethylpyrazol-1-yl)acetate (bdmpza) and bis(pyrazol-1-yl)acetate (bpza) to Group VII metal carbonyls was studied. [LM(CO)3], where M = Mn, Re and L = bpza, bdmpza (2a-3b), were synthesized. [(Bdmpza)Mn(CO)3] (2b), [(bpza)Re(CO)3] (3a) and [(bdmpza)Re(CO)3] (3b), and bis(pyrazol-1-yl)acetic acid (1a) were characterized by single-crystal x-ray analyses. Based on IR-spectroscopic and structural data the electronic properties of these ligands are compared with those of Tp, TpMe2, Cp and Cp*. The reaction of [(bdmpza)Re(CO)3] (3b) with NOBF4 afforded [(bdmpza)Re(CO)2(NO)]BF4 (4).
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      Molecular core binding energies for some five-membered ring heterocycles as determined by x-ray photoelectron spectroscopy
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      Chemical Physics Letters (1971), 9 (3), 234-7CODEN: CHPLBC; ISSN:0009-2614.
      The binding energies, detd. by x-ray photoelectron spectroscopy, for the C, S, N, and O atoms in thiophene, pyrrole, furan, isoxazole, pyrazole, imidazole, and thiazole reflect the variations in the electronegativities of the heteroatoms. The exptl. mol. core binding energies are correlated with the variations in the orbital energies and with the variations in the at. charge distributions, which were obtained from nonempirical and semiempirical LCAO MO calcns.
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      Polzonetti, G.; Battocchio, C.; Goldoni, A.; Larciprete, R.; Carravetta, V.; Paolesse, R.; Russo, M. V. Interface formation between C60 and diethynyl-Zn-porphyrinato investigated by SR-induced photoelectron and near-edge X-ray absorption (NEXAFS) spectroscopies. Chem. Phys. 2004, 297, 307– 314,  DOI: 10.1016/j.chemphys.2003.10.024
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      Interface formation between C60 and diethynyl-Zn-porphyrinato investigated by SR-induced photoelectron and near-edge X-ray absorption (NEXAFS) spectroscopies
      Polzonetti, G.; Battocchio, C.; Goldoni, A.; Larciprete, R.; Carravetta, V.; Paolesse, R.; Russo, M. V.
      Chemical Physics (2004), 297 (1-3), 307-314CODEN: CMPHC2; ISSN:0301-0104. (Elsevier Science B.V.)
      C60 doping of multilayer 2,8,12,18-tetraethyl-5,15-diethynyl-3,7,13,17-tetramethylporphyrinato-Zn(II) (Zn-Pf) has been accomplished. The sublimed Zn-Pf mols. initially lay flat on the Cu(1 1 1) substrate and progressively tilt their arrangement in order to be oriented with the mol. plane nearly perpendicular to the Cu(1 1 1) substrate surface, at both monolayer and multilayer coverage, as detected by NEXAFS spectroscopy at the N K-edge. It is noteworthy that C60 interacts with the Zn-Pf sample film producing a perturbation of the electronic structure reflected in the spectral changes at the C1s core level, at the N1s and shake-up satellites of Zn-Pf and in the VB region. By the strong spectral modification that occurs at the Zn-Pf multilayer sample C60 diffusion into the substrate is also argued, giving rise most probably to an intercalated composite assembly with C60 spheres in between two Zn-Pf planes. The obsd. changes are interpreted in terms of charge transfer taking place from C60 to Zn-Pf with a lowering of the band gap and presence of occupied states closer to EF.
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      Battocchio, C.; Fratoddi, I.; Iucci, G.; Russo, M. V.; Goldoni, A.; Parent, P.; Polzonetti, G. Dinuclear Pt and Pd complexes with metalloporphyrin bridges: A NEXAFS study of the electronic structure and self-assembling properties. Mater. Sci. Eng., C 2007, 27, 1338– 1342,  DOI: 10.1016/j.msec.2006.06.014
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      Dinuclear Pt and Pd complexes with metalloporphyrin bridges: A NEXAFS study of the electronic structure and self-assembling properties
      Battocchio, C.; Fratoddi, I.; Iucci, G.; Russo, M. V.; Goldoni, A.; Parent, Ph.; Polzonetti, G.
      Materials Science & Engineering, C: Biomimetic and Supramolecular Systems (2007), 27 (5-8), 1338-1342CODEN: MSCEEE; ISSN:0928-4931. (Elsevier B.V.)
      Binuclear Zn-porphinate-bridged platinum and palladium acetylides were prepd. and studied by K-edge NEXAFS spectroscopy. The complexes, cis,cis-[(PBu3)2ClPtC≡CXC≡CPtCl(PBu3)2] (Pt-ZnDEP) and trans,trans-[(PBu3)2(R)PdC≡CXC≡CPd(R)(PBu3)2] [Pt-ZnDEP, Pd-ZnDEP, resp., X = Zn(2+)-2,8,12,18-tetraethyl-3,7,13,17-tetramethylporphinate(2-)-5,15-diyl; R = PhC≡C] were prepd. by coupling of the diyne HC≡CXC≡CH (ZnDEP) and [(PBu3)2PtCl2] and [(PBu3)2(R)PdCl], resp. The complexes Pt-ZnDEP and Pd-ZnDEP were investigated by means of Near Edge X-ray Absorption Fine Structure spectroscopy (NEXAFS). N K-edge spectra collected on the two macromol. arrays were compared with data on ZnDEP and 2,8,12,18-tetraethyl-5,15-diethynyl-3,7,13,17-tetramethylporphyrin (DEP); an energy shift towards higher photon energy values was obsd. and attributed to charge transfer from the tetrapyrrolic macrocycle to the transition metal terminal groups. Angular dependent NEXAFS characterization of both Pd-ZnDEP and Pt-ZnDEP films deposited on gold allowed to assess that the macromols. grow in ordered layers.
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      Gabrielli, S.; Pellei, M.; Venditti, I.; Fratoddi, I.; Battocchio, C.; Iucci, G.; Schiesaro, I.; Meneghini, C.; Palmieri, A.; Marcantoni, E.; Bagnarelli, L.; Vallesi, R.; Santini, C. Development of new and efficient copper(II) complexes of hexyl bis(pyrazolyl)acetate ligands as catalysts for allylic oxidation. Dalton Trans. 2020, 49, 15622– 15632,  DOI: 10.1039/d0dt02952a
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      Development of new and efficient copper(II) complexes of hexyl bis(pyrazolyl)acetate ligands as catalysts for allylic oxidation
      Gabrielli, Serena; Pellei, Maura; Venditti, Iole; Fratoddi, Ilaria; Battocchio, Chiara; Iucci, Giovanna; Schiesaro, Irene; Meneghini, Carlo; Palmieri, Alessandro; Marcantoni, Enrico; Bagnarelli, Luca; Vallesi, Riccardo; Santini, Carlo
      Dalton Transactions (2020), 49 (44), 15622-15632CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
      In this study, two new hexyl bis(pyrazol-1-yl)acetate ligands and related copper(II) complexes were prepd. and fully characterized in the solid state and in soln. Their electronic and mol. structures were investigated by XPS and near edge X-ray absorption; their ligand mol. structural stability upon coordination to copper was also investigated. The Cu(II) complexes were studied as new catalysts in copper-catalyzed C-H oxidn. for allylic functionalization (the Kharasch-Sosnovsky reaction) avoiding the use of any external reducing agents. Using 5 mol% of these catalysts and tert-butylperoxybenzoate as the oxidant, allylic benzoates were obtained in up to 90% yield: the general reaction time was decreased to 6 h and a 5 to 1 ratio of the alkene and tert-butylperoxybenzoate was used to overcome the two most important limitations on their use in chem.
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      NIST X-ray Photoelectron Spectroscopy Database, version 4.1; National Institute of Standards and Technology. http://srdata.nist.gov/xps/.=NIST.
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      Decomposition of copper compounds in x-ray photoelectron spectrometers
      Klein, Joseph C.; Li, Chung Ping; Hercules, David M.; Black, James F.
      Applied Spectroscopy (1984), 38 (5), 729-34CODEN: APSPA4; ISSN:0003-7028.
      Six Cu compds. were analyzed in 3 different x-ray photoelectron spectrometers (AEI-ES200, LHS-10, and HP-5950A), each equipped with a different type of Al Kα x-ray source, to det. the cause of redn. of Cu salts in photoelectron spectrometers. The monochromatic source used in the HP 5950A spectrometer did not cause sample degrdn. Significant sample degrdn. was obsd. in the AEI ES200, which was attributed to the radiative heating from the x-ray gun. The LHS-10 spectrometer, which utilizes a water-cooled x-ray housing, afforded significantly less sample redn. than the AEI ES200 spectrometer.
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      Syugaev, A. V.; Maratkanova, A. N.; Smirnov, D. A. Molecular orientation in electrodeposited polypyrrole films. J. Solid State Electrochem. 2018, 22, 2127– 2134,  DOI: 10.1007/s10008-018-3925-z
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      Molecular orientation in electrodeposited polypyrrole films
      Syugaev, A. V.; Maratkanova, A. N.; Smirnov, D. A.
      Journal of Solid State Electrochemistry (2018), 22 (7), 2127-2134CODEN: JSSEFS; ISSN:1432-8488. (Springer)
      The mol. arrangement in electrodeposited polypyrrole films was studied by means of linear dichroism in the near-edge X-ray absorption fine structure (NEXAFS) spectra measured at the K absorption edges of carbon and nitrogen. It has been found that the change of the exciting radiation incidence from normal to grazing leads to an increase in the intensity of π*-related resonances with simultaneous decrease in the intensity of σ*-related resonances in the spectra. Similar changes in the spectra measured for both absorption edges indicate a pronounced conjugation of π-bonds in the polypyrrole chains in the grown films. Preferential in-plane orientation of pyrrole rings relative to the substrate surface is obsd. for all the deposited films. The linear dichroism is more pronounced at the initial stages of deposition (2D growth) than at later stages characterized by "cauliflower"-like morphol. of the grown film.
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      Pavlychev, A. A.; Hallmeier, K. H.; Hennig, C.; Hennig, L.; Szargan, R. Nitrogen K-shell excitations in complex molecules and polypyrrole. Chem. Phys. 1995, 201, 547– 555,  DOI: 10.1016/0301-0104(95)00287-1
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      Nitrogen K-shell excitations in complex molecules and polypyrrole
      Pavlychev, A. A.; Hallmeier, K. H.; Hennig, C.; Hennig, L.; Szargan, R.
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      Exptl. and theor. studies of N K-shell near-edge absorption in complex compds. such as thiourea, benzalaniline, pyrrole, polypyrrole, Et4N+, Bu4N and substituted 2-hydroxy-3-methoxy-benzylidene-aniline compds. were carried out. The quasi-at. model was used to calc. the spectral distribution of oscillator strengths for transitions from the N 1s level to excited discrete and continuum states, to explain general trends in the changes of K-shell excitation spectra and to reveal their relations with chem. bonding of the N atom in the compds. The performed anal. of theor. and exptl. spectra evidences the central role of splitting of an intense N 1s-12p resonance in N K XANES formation in all compds. under study. The influence of the electronic charge transfer, bond conjugation and localization on the energies and intensities of π* and σ* resonances are discussed. The strong connection between interference and chem. bonding effects on the main resonance features of x-ray absorption in the compds. under study is revealed.
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      Franchi, S.; Secchi, V.; Santi, M.; Dettin, M.; Zamuner, A.; Battocchio, C.; Iucci, G. Biofunctionalization of TiO2 surfaces with self-assembling oligopeptides in different pH and Ionic Strength conditions: Charge effects and molecular organization. Mater. Sci. Eng., C 2018, 90, 651– 656,  DOI: 10.1016/j.msec.2018.05.006
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      Biofunctionalization of TiO2 surfaces with self-assembling oligopeptides in different pH and Ionic Strength conditions: Charge effects and molecular organization
      Franchi, S.; Secchi, V.; Santi, M.; Dettin, M.; Zamuner, A.; Battocchio, C.; Iucci, G.
      Materials Science & Engineering, C: Materials for Biological Applications (2018), 90 (), 651-656CODEN: MSCEEE; ISSN:0928-4931. (Elsevier B.V.)
      Self-assembling peptides (SAPs) were investigated by means of XPS and Angular Dependent NEXAFS spectroscopies, with the aim to probe the influence of pH and Ionic Strength conditions on the chem. structure and mol. organization of SAPs anchored on titania surfaces. XPS at the C1s, N1s, O1s core levels allowed to study surfaces and biomol./substrate interfaces. NEXAFS data allowed ascertaining that SAPs mol. structure is preserved upon grafting to the titania surface. Angular Dependent NEXAFS was used to investigate the influence of environmental conditions on the mol. organization behavior. The objective of our study was to establish a set of methodologies for obtaining arrangements of well-organized biomols. on scaffolds surfaces as a basic technol. to develop and optimize cells adhesion and proliferation for tissue engineering applications.
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      Benfatto, M.; Meneghini, C. In Synchrotron Radiation: Basics, Methods and Applications; Mobilio, S., Boscherini, F., Meneghini, C., Eds.; Springer Berlin Heidelberg: Berlin, Heidelberg, 2015; pp 213– 240.
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      Chaboy, J.; Muñoz-Páez, A.; Carrera, F.; Merkling, P.; Marcos, E. S. Ab initiox-ray absorption study of copperK-edge XANES spectra in Cu(II) compounds. Phys. Rev. B: Condens. Matter Mater. Phys. 2005, 71, 134208,  DOI: 10.1103/PhysRevB.71.134208
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      Ab initio x-ray absorption study of copper K-edge XANES spectra in Cu(II) compounds
      Chaboy, Jesus; Munoz-Paez, Adela; Carrera, Flora; Merkling, Patrick; Marcos, Enrique Sanchez
      Physical Review B: Condensed Matter and Materials Physics (2005), 71 (13), 134208/1-134208/7CODEN: PRBMDO; ISSN:1098-0121. (American Physical Society)
      This work reports a theor. study of the x-ray absorption near-edge structure spectra at the Cu K edge in several Cu(II) complexes with N-coordinating ligands showing a square-planar arrangement around metal cation. It is shown that single-channel multiple-scattering calcns. are not able to reproduce the exptl. spectra. The comparison between exptl. data and ab initio computations indicates the need of including the contribution of two electronic configurations (3d9 and 3d10L) to account for a proper description of the final state during the photoabsorption process. The best agreement between theory and expt. is obtained by considering a relative wt. of 68% and 32% for the two absorption channels 3d10L and 3d9, resp.
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      Giorgetti, M.; Guadagnini, L.; Fiddy, S. G.; Santini, C.; Pellei, M. Cu K-edge EXAFS on copper(I) complexes containing dihydridobis(3-nitro-1,2,4-triazol-1-yl)borate and bis(1,2,4-triazol-1-yl)acetate ligand: Evidence for the Cu-O interaction. Polyhedron 2009, 28, 3600– 3606,  DOI: 10.1016/j.poly.2009.07.032
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      Cu K-edge EXAFS on copper(I) complexes containing dihydridobis(3-nitro-1,2,4-triazol-1-yl)borate and bis(1,2,4-triazol-1-yl)acetate ligand: Evidence for the Cu-O interaction
      Giorgetti, Marco; Guadagnini, Lorella; Fiddy, Steven G.; Santini, Carlo; Pellei, Maura
      Polyhedron (2009), 28 (16), 3600-3606CODEN: PLYHDE; ISSN:0277-5387. (Elsevier B.V.)
      X-ray absorption spectroscopy (XAS) has been used to probe the local structure of copper(I) complexes contg. the dihydridobis(3-nitro-1,2,4-triazol-1-yl)borate and the bis(1,2,4-triazol-1-yl)acetate ligands. The material is polycryst. and no crystal structure is available in the literature. The EXAFS anal. has permitted the identification of the local environment of the copper site. Copper is found to be 4-fold coordinated with two sets of Cu-N and Cu-P interactions describing a quasi planar figure. An addnl. coordination is revealed for the copper(I) complex of bis(1,2,4-triazol-1-yl)acetate due to the interaction of the copper with the acetate of the scorpionate ligand. XANES spectra of the studied samples show a resolved pre-edge peak at about 8983 eV which is assigned to the 1s → 4p transition, whose intensities can be explained considering the copper in a 4-fold coordination.
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    69. 69
      Kau, L. S.; Spira-Solomon, D. J.; Penner-Hahn, J. E.; Hodgson, K. O.; Solomon, E. I. X-ray absorption edge determination of the oxidation state and coordination number of copper. Application to the type 3 site in Rhus vernicifera laccase and its reaction with oxygen. J. Am. Chem. Soc. 1987, 109, 6433– 6442,  DOI: 10.1021/ja00255a032
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      X-ray absorption edge determination of the oxidation state and coordination number of copper. Application to the type 3 site in Rhus vernicifera laccase and its reaction with oxygen
      Kau, Lung Shan; Spira-Solomon, Darlene J.; Penner-Hahn, James E.; Hodgson, Keith O.; Solomon, Edward I.
      Journal of the American Chemical Society (1987), 109 (21), 6433-42CODEN: JACSAT; ISSN:0002-7863.
      Cu x-ray absorption edge features of 19 Cu(I) and 40 Cu(II) model complexes were systematically studied and correlated with oxidn. state and geometry. Studies of Cu(I) model complexes with different coordination no. revealed that an 8983-8984-eV peak (assigned as the Cu 1s → 4p transition) could be correlated in energy, shape, and intensity with ligation and site geometry of the Cu(I). These Cu(I) edge features were qual. interpreted with ligand field concepts. Alternatively, no Cu(II) complex exhibited a peak at <8985.0 eV. The limited intensity obsd. in the 8983-8985-eV region for some Cu(II) complexes was assocd. with the tail of an absorption peak at ∼8986 eV which was affected by the covalency of the equatorial ligands. These model studies allowed accurate calibration of a normalized difference edge procedure which is used for the quant. detn. of Cu(I) content in Cu complexes of mixed oxidn. state compn. This normalized difference edge anal. was then used to quant. det. the oxidn. states of the Cu sites in type 2 Cu-depleted (T2D) and native forms of the multi-Cu-contg. oxidase, R. vernicifera laccase. The type 3 (T3) site of T2D laccase was found to be fully reduced and stable to oxidn. by O2 or by 25-fold protein equiv. of ferricyanide, but it could be oxidized by reaction with peroxide. The increase in intensity of the 330-nm absorption feature which resulted from peroxide titrn. of T2D laccase was linearly correlated with the percent of oxidn. of the binuclear Cu site. This correlation indicated that peroxide oxidizes but does not bind to the T3 site. This correlation was used to det. that native laccase, as isolated, contains 22% reduced T3 sites and that all spectral changes obsd. upon peroxide addn. to native laccase can be accounted for by oxidn. of these reduced sites. In the presence of azide and peroxide, further redn. occurs and as many as 40% of the binuclear Cu pairs are stabilized in the reduced state. The importance of these results to previous reports of peroxide binding at the laccase active site is discussed.
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      Fornasini, P. Synchrotron Radiation: Basics, Methods and Applications; Springer Berlin Heidelberg, 2015; pp 181– 211.
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      Noordhuis, P.; Laan, A. C.; van de Born, K.; Losekoot, N.; Kathmann, I.; Peters, G. J. Oxaliplatin activity in selected and unselected human ovarian and colorectal cancer cell lines. Biochem. Pharmacol. 2008, 76, 53– 61,  DOI: 10.1016/j.bcp.2008.04.007
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      Oxaliplatin activity in selected and unselected human ovarian and colorectal cancer cell lines
      Noordhuis, Paul; Laan, Adri C.; van de Born, Kasper; Losekoot, Nienke; Kathmann, Ietje; Peters, Godefridus J.
      Biochemical Pharmacology (2008), 76 (1), 53-61CODEN: BCPCA6; ISSN:0006-2952. (Elsevier)
      Oxaliplatin is used for treatment of colon cancer in combination with 5-fluorouracil or irinotecan. Oxaliplatin has similar, but also different resistant mechanisms as cisplatin. We studied the activity of oxaliplatin in ovarian and colon cancer cells with different resistance patterns to cisplatin. The 40-fold cisplatin-resistant cell line ADDP was only 7.5-fold resistant to oxaliplatin. The gemcitabine-resistant AG6000 cell line, 9-fold resistant to cisplatin, was not cross-resistant. LoVo-175X2, with mutant p53 showed no resistance compared to the empty vector control. However, LoVo-Li, with inactive p53, was 3.6-fold resistant corresponding to decreased accumulation and Pt adducts. Accumulation and DNA adducts formation showed no significant correlation with oxaliplatin sensitivity. Cell cycle distribution after exposure to oxaliplatin showed arrest in G2/M (A2780) or in S-phase (LoVo-92) for wt-p53 cells. ADDP and LoVo-Li showed G1 arrest followed by S-phase arrest and no changes in distribution, resp. The cell cycle related proteins Cyclins A and B1 and (p)CDC25C were marginally affected by oxaliplatin. Expression of hCTR1 was decreased in ADDP, LoVo-Li and AG6000, OCT1 decreased in ADDP and AG6000 and OCT3 in LoVo-175X2, compared to the parental cell lines. In ADDP and LoVo-175X2 ATP7A and B were decreased but were increased in AG6000. From this study it can be concluded that changes in cell cycle distribution were cell line dependent and not related to changes in expression of Cyclin A or B1. Oxaliplatin accumulation was related to hCTR1 and, at low concn., ATP7A to DNA adducts formation while the retention was related to hCTR1, OCT2 and ATP7B.
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      Wersinger, C.; Rebel, G.; Lelong-Rebel, I. Detailed study of the different taurine uptake systems of colon LoVo MDR and non-MDR cell lines. Amino Acids 2000, 19, 667– 685,  DOI: 10.1007/s007260070015
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      Detailed study of the different taurine uptake systems of colon LoVo MDR and non-MDR cell lines
      Wersinger, C.; Rebel, G.; Lelong-Rebel, I. H.
      Amino Acids (2000), 19 (3-4), 667-685CODEN: AACIE6; ISSN:0939-4451. (Springer-Verlag Wien)
      In human, physiol. taurine requirement is partly dependent on nutrition. Study of the human carcinoma LoVo cells shows the presence of a high and a low affinity taurine uptake. Besides them, a diffusion system has been found. A detailed anal. of the properties of the three systems is presented. A comparison of LoVo chemosensitive cells, and LoVo chemoresistant (MDR) cells which overexpress the multidrug transporter P-glycoprotein, shows that the only difference between the two cell types belong to the kinetic properties of the high and low affinity taurine uptake systems.
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    73. 73
      Marzano, C.; Pellei, M.; Colavito, D.; Alidori, S.; Lobbia, G. G.; Gandin, V.; Tisato, F.; Santini, C. Synthesis, characterization, and in vitro antitumor properties of tris(hydroxymethyl)phosphine copper(I) complexes containing the new bis(1,2,4-triazol-1-yl)acetate ligand. J. Med. Chem. 2006, 49, 7317– 7324,  DOI: 10.1021/jm0601248
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      Synthesis, Characterization, and in Vitro Antitumor Properties of Tris(hydroxymethyl)phosphine Copper(I) Complexes Containing the New Bis(1,2,4-triazol-1-yl)acetate Ligand
      Marzano, Cristina; Pellei, Maura; Colavito, Davide; Alidori, Simone; Lobbia, Giancarlo Gioia; Gandin, Valentina; Tisato, Francesco; Santini, Carlo
      Journal of Medicinal Chemistry (2006), 49 (25), 7317-7324CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      The new sodium bis(1,2,4-triazol-1-yl)acetate ligand, Na[HC(CO2)(tz)2], has been prepd. in methanol soln. by using 1,2,4-triazole, dibromoacetic acid and NaOH. Treatment of the [Cu(CH3CN)4][PF6] acceptor with Na[HC(CO2)(tz)2] or Na[HC(CO2)(pzMe2)2] in the presence of the tris(hydroxymethyl)phosphine coligand in methanol/acetonitrile solns. produced unprecedented mononuclear copper(I) complexes of the type [HC(CO2)(tz)2]Cu[P(CH2OH)3]2 (2), [HC(CO2)(pzMe2)2]Cu[P(CH2OH)3]2 (3) and [(CH3CN)2Cu(P(CH2OH)3)2]PF6 (4). These compds. have been characterized by elemental analyses, FTIR, ESI-MS, and multinuclear (1H and 31P) NMR spectral data. The new copper(I) complexes were tested for their cytotoxic properties against a panel of several human tumor cell lines. The results reported here indicate that all the complexes showed in vitro antitumor activity similar or better than that of cisplatin, the most used metal-based antitumor drug. In particular, complex 3 showed IC50 values markedly lower than the ref. compd. against all tumor cell lines. Chemosensitivity tests performed on cisplatin sensitive and resistant cell lines have demonstrated that all these Cu(I) complexes were able to overcome cisplatin resistance, supporting the hypothesis of a different mechanism of action compared to that exhibited by the ref. drug. Flow cytometric anal. on 2008 human ovarian carcinoma cells revealed that complex 3, chosen as the best candidate, induced a marked enlargement of both cell size and granularity and a significant increase in the fraction of G2/M cells that, differently from cisplatin, was not accompanied by the appearance of a relevant sub-G1 fraction. No evidence of caspase-3 activation was detected in cells treated with complex 3. We hypothesize that the cytotoxic activity of the new copper(I) complex may be correlated to its ability to trigger paraptosis, a non-apoptotic mechanism of cell death.
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    74. 74
      Pellei, M.; Gandin, V.; Cimarelli, C.; Quaglia, W.; Mosca, N.; Bagnarelli, L.; Marzano, C.; Santini, C. Syntheses and biological studies of nitroimidazole conjugated heteroscorpionate ligands and related Cu(I) and Cu(II) complexes. J. Inorg. Biochem. 2018, 187, 33– 40,  DOI: 10.1016/j.jinorgbio.2018.07.008
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      Syntheses and biological studies of nitroimidazole conjugated heteroscorpionate ligands and related Cu(I) and Cu(II) complexes
      Pellei, Maura; Gandin, Valentina; Cimarelli, Cristina; Quaglia, Wilma; Mosca, Nello; Bagnarelli, Luca; Marzano, Cristina; Santini, Carlo
      Journal of Inorganic Biochemistry (2018), 187 (), 33-40CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier)
      Cu(I) and Cu(II) complexes of 5-nitroimidazole conjugated heteroscorpionate ligands were synthesized. In particular, the new 2,2-bis(pyrazol-1-yl)-N-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)acetamide ligand (LHMN) was synthesized by direct coupling of preformed side chain acid with 5-nitroimidazole and its coordination chem. was studied towards Cu(I) and Cu(II) acceptors and compared with that of the related 2,2-bis(3,5-dimethyl-1-H-pyrazol-1-yl)-N-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)acetamide ligand (LMeMN). The Cu(II) complexes {[(LMeMN)2Cu]Cl2} and {[(LHMN)2Cu]Cl2} were prepd. by the reaction of CuCl2·2H2O with LHMN or LMeMN ligands in MeOH soln. The water sol. Cu(I) complexes {[(LMeMN)Cu(PTA)2]}(PF6) and {[(LHMN)Cu(PTA)2]}(PF6) were prepd. by the reaction of Cu(MeCN)4PF6 and 1,3,5-triaza-7-phosphaadamantane (PTA) with LHMN or LMeMN ligands in MeCN soln. The new Cu(I) and Cu(II) complexes as well as the corresponding uncoordinated ligands were evaluated for their cytotoxic activity against 2-dimensional monolayer cultures of multiple human cancer cell lines and 3-dimensional-cultured HCT-15 colon cancer spheroids. Morphol. anal. by TEM revealed the induction of a massive cytoplasmic vacuolization consistent with a paraptotic-like cancer cell death.
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      Zanoni, M.; Cortesi, M.; Zamagni, A.; Arienti, C.; Pignatta, S.; Tesei, A. Modeling neoplastic disease with spheroids and organoids. J. Hematol. Oncol. 2020, 13, 97,  DOI: 10.1186/s13045-020-00931-0
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      Modeling neoplastic disease with spheroids and organoids
      Zanoni Michele; Cortesi Michela; Zamagni Alice; Arienti Chiara; Pignatta Sara; Tesei Anna
      Journal of hematology & oncology (2020), 13 (1), 97 ISSN:.
      Cancer is a complex disease in which both genetic defects and microenvironmental components contribute to the development, progression, and metastasization of disease, representing major hurdles in the identification of more effective and safer treatment regimens for patients. Three-dimensional (3D) models are changing the paradigm of preclinical cancer research as they more closely resemble the complex tissue environment and architecture found in clinical tumors than in bidimensional (2D) cell cultures. Among 3D models, spheroids and organoids represent the most versatile and promising models in that they are capable of recapitulating the heterogeneity and pathophysiology of human cancers and of filling the gap between conventional 2D in vitro testing and animal models. Such 3D systems represent a powerful tool for studying cancer biology, enabling us to model the dynamic evolution of neoplastic disease from the early stages to metastatic dissemination and the interactions with the microenvironment. Spheroids and organoids have recently been used in the field of drug discovery and personalized medicine. The combined use of 3D models could potentially improve the robustness and reliability of preclinical research data, reducing the need for animal testing and favoring their transition to clinical practice. In this review, we summarize the recent advances in the use of these 3D systems for cancer modeling, focusing on their innovative translational applications, looking at future challenges, and comparing them with most widely used animal models.
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      Öhrvik, H.; Aaseth, J.; Horn, N. Orchestration of dynamic copper navigation─new and missing pieces. Metallomics 2017, 9, 1204– 1229,  DOI: 10.1039/c7mt00010c
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      Orchestration of dynamic copper navigation - new and missing pieces
      Ohrvik Helena; Aaseth Jan; Horn Nina
      Metallomics : integrated biometal science (2017), 9 (9), 1204-1229 ISSN:.
      A general principle in all cells in the body is that an essential metal - here copper - is taken up at the plasma membrane, directed through cellular compartments for use in specific enzymes and pathways, stored in specific scavenging molecules if in surplus, and finally expelled from the cells. Here we attempt to provide a critical view on key concepts involved in copper transfer across membranes and through compartments in the human body. The focus of this review is on the influence of bioinorganic and thermodynamic rules on the flow in cellular copper networks. Transition of copper from one oxidation state to another will often lead to errant electrons that are highly reactive and prone to form radicals and reactive oxygen or nitrogen species (ROS and RNS). Strict control of potentially toxic oxidative species is an important part of understanding the edge of human copper metabolism. The present review critically covers translocation across simple and complex membranes as well as extracellular and intracellular copper routing. We discuss in depth four tissues with polarized cell barriers - the gut, liver, kidneys, and brain - to illustrate the similarities and differences in transcellular transfer. Copper chaperoning, buffering and binding dynamics to guide the metal to different sites are also covered, while individual molecular interaction kinetics are not detailed. Sorting and targeting mechanisms and principles crucial for correct localisation will also be touched upon.
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    77. 77
      Xu, H. N.; Feng, M.; Nath, K.; Nelson, D.; Roman, J.; Zhao, H.; Lin, Z.; Glickson, J.; Li, L. Z. Optical Redox Imaging of Lonidamine Treatment Response of Melanoma Cells and Xenografts. Mol. Imaging Biol. 2019, 21, 426– 435,  DOI: 10.1007/s11307-018-1258-z
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      Optical Redox Imaging of Lonidamine Treatment Response of Melanoma Cells and Xenografts
      Xu, He N.; Feng, Min; Nath, Kavindra; Nelson, David; Roman, Jeff; Zhao, Huaqing; Lin, Zhenwu; Glickson, Jerry; Li, Lin Z.
      Molecular Imaging and Biology (2019), 21 (3), 426-435CODEN: MIBOCZ; ISSN:1860-2002. (Springer)
      Fluorescence of co-enzyme reduced NAD (NADH) and oxidized flavoproteins (Fp) provides a sensitive measure of the mitochondrial redox state and cellular metab. By imaging NADH and Fp, we investigated the utility of optical redox imaging (ORI) to monitor cellular metab. and detect early metabolic response to cancer drugs. We performed ORI of human melanoma DB-1 cells in culture and DB-1 mouse xenografts to detect the redox response to lonidamine (LND) treatment. For cultured cells, LND treatment for 45 min significantly lowered NADH levels with no significant change in Fp, resulting in a significant increase in the Fp redox ratio (Fp/(NADH+Fp)); 3-h prolonged treatment led to a decrease in NADH and an increase in Fp and a more oxidized redox state compared to control. Significant decrease in the mitochondrial redox capacity of LND-treated cells was obsd. for the first time. For xenografts, 45-min LND treatment resulted in a significant redn. of NADH content, no significant changes in Fp content, and a trend of increase in the Fp redox ratio. Intratumor redox heterogeneity was obsd. in both control and LND-treated groups. Our results support the utility of ORI for evaluating cellular metab. and monitoring early metabolic response to cancer drugs.
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      Nordberg, J.; Arnér, E. S. J. Reactive oxygen species, antioxidants, and the mammalian thioredoxin system1 1This review is based on the licentiate thesis “Thioredoxin reductase-interactions with the redox active compounds 1-chloro-2,4-dinitrobenzene and lipoic acid” by Jonas Nordberg, 2001, Karolinska Institute, Stockholm, ISBN 91-631-1064-4. Free Radical Biol. Med. 2001, 31, 1287– 1312,  DOI: 10.1016/s0891-5849(01)00724-9
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      Reactive oxygen species, antioxidants, and the mammalian thioredoxin system
      Nordberg, Jonas; Arner, Elias S. J.
      Free Radical Biology & Medicine (2001), 31 (11), 1287-1312CODEN: FRBMEH; ISSN:0891-5849. (Elsevier Science Inc.)
      A review. Reactive oxygen species (ROS) are known mediators of intracellular signaling cascades. Excessive prodn. of ROS may, however, lead to oxidative stress, loss of cell function, and ultimately apoptosis or necrosis. A balance between oxidant and antioxidant intracellular systems is hence vital for cell function, regulation, and adaptation to diverse growth conditions. Thioredoxin reductase (TrxR) in conjunction with thioredoxin (Trx) is a ubiquitous oxidoreductase system with antioxidant and redox regulatory roles. In mammals, extracellular forms of Trx also have cytokine-like effects. Mammalian TrxR has a highly reactive active site selenocysteine residue resulting in a profound reductive capacity, reducing several substrates in addn. to Trx. Due to the reactivity of TrxR, the enzyme is inhibited by many clin. used electrophilic compds. including nitrosoureas, aurothioglucose, platinum compds., and retinoic acid derivs. The properties of TrxR in combination with the functions of Trx position this system at the core of cellular thiol redox control and antioxidant defense. In this review, the authors focus on the reactions of the Trx system with ROS mols. and different cellular antioxidant enzymes. The authors summarize the TrxR-catalyzed regeneration of several antioxidant compds., including ascorbic acid (vitamin C), selenium-contg. substances, lipoic acid, and ubiquinone (Q10). The general cellular effects of TrxR inhibition are also discussed. Dinitrohalobenzenes constitute a unique class of immunostimulatory TrxR inhibitors and the authors consider the immunomodulatory effects of dinitrohalobenzene compds. in view of their reactions with the Trx system.
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      Fontana, F.; Raimondi, M.; Marzagalli, M.; Di Domizio, A.; Limonta, P. The emerging role of paraptosis in tumor cell biology: Perspectives for cancer prevention and therapy with natural compounds. Biochim. Biophys. Acta, Rev. Cancer 2020, 1873, 188338,  DOI: 10.1016/j.bbcan.2020.188338
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      The emerging role of paraptosis in tumor cell biology: Perspectives for cancer prevention and therapy with natural compounds
      Fontana, Fabrizio; Raimondi, Michela; Marzagalli, Monica; Di Domizio, Alessandro; Limonta, Patrizia
      Biochimica et Biophysica Acta, Reviews on Cancer (2020), 1873 (2), 188338CODEN: BBACEU; ISSN:0304-419X. (Elsevier B.V.)
      A review. Std. anti-cancer therapies promote tumor growth suppression mainly via induction of apoptosis. However, in most cases cancer cells acquire the ability to escape apoptotic cell death, thus becoming resistant to current treatments. In this setting, the interest in alternative cell death modes has recently increased. Paraptosis is a new form of programmed cell death displaying endoplasmic reticulum (ER) and/or mitochondria dilation, generally due to proteostasis disruption or redox and ion homeostasis alteration. Recent studies have highlighted that several natural compds. can trigger paraptosis in different tumor cell lines. Here, we review the mol. mechanisms underlying paraptotic cell death, as well as the natural products inducing this kind of cell death program. A better understanding of paraptosis should facilitate the development of new therapeutic strategies for cancer prevention and treatment.
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      Moulder, J. F.; Stickle, W. F.; Sobol, P. E.; Bomben, K. D. Handbook of X-Ray Photoelectron Spectroscopy; Eden Prairie, 1996.
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      Beamson, G.; Briggs, D. In Surface and Interface Analysis; Watts, J. F., Ed.; John Wiley & Sons: Chichester, 1992; Vol. 20, p 267.
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      Shirley, D. A. High-resolution x-ray photoemission spectrum of the valence bands of gold. Phys. Rev. B: Solid State 1972, 5, 4709– 4714,  DOI: 10.1103/PhysRevB.5.4709
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      Dent, A. J.; Cibin, G.; Ramos, S.; Smith, A. D.; Scott, S. M.; Varandas, L.; Pearson, M. R.; Krumpa, N. A.; Jones, C. P.; Robbins, P. E. B18: A core XAS spectroscopy beamline for Diamond. J. Phys.: Conf. Ser. 2009, 190, 012039,  DOI: 10.1088/1742-6596/190/1/012039
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      Cicco, A. D.; Aquilanti, G.; Minicucci, M.; Principi, E.; Novello, N.; Cognigni, A.; Olivi, L. Novel XAFS capabilities at ELETTRA synchrotron light source. J. Phys.: Conf. Ser. 2009, 190, 012043,  DOI: 10.1088/1742-6596/190/1/012043
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      Meneghini, C.; Bardelli, F.; Mobilio, S. ESTRA-FitEXA: A software package for EXAFS data analysis. Nucl. Instrum. Methods Phys. Res., Sect. B 2012, 285, 153– 157,  DOI: 10.1016/j.nimb.2012.05.027
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      ESTRA-FitEXA: A software package for EXAFS data analysis
      Meneghini, C.; Bardelli, F.; Mobilio, S.
      Nuclear Instruments & Methods in Physics Research, Section B: Beam Interactions with Materials and Atoms (2012), 285 (), 153-157CODEN: NIMBEU; ISSN:0168-583X. (Elsevier B.V.)
      ESTRA and FitEXA are two programs for processing X-ray absorption spectroscopy data, extn. of extended X-ray absorption fine structure (EXAFS) signal, and EXAFS data anal. via least square refinement procedure (shell fitting). ESTRA and FitEXA propose useful options such as the anal. of the noise on the raw χ(k) data and a high flexibility in the choice of the model distribution function: harmonic, anharmonic (cumulants) and hard sphere models. The minimization routines underneath the FitEXA code allow ample choice/control of the non-linear minimization procedure and check of the correlation among the parameters.
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      Ankudinov, A. L.; Ravel, B.; Rehr, J. J.; Conradson, S. D. Real-space multiple-scattering calculation and interpretation of x-ray-absorption near-edge structure. Phys. Rev. B: Condens. Matter Mater. Phys. 1998, 58, 7565– 7576,  DOI: 10.1103/PhysRevB.58.7565
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      Real-space multiple-scattering calculation and interpretation of x-ray-absorption near-edge structure
      Ankudinov, A. L.; Ravel, B.; Rehr, J. J.; Conradson, S. D.
      Physical Review B: Condensed Matter and Materials Physics (1998), 58 (12), 7565-7576CODEN: PRBMDO; ISSN:0163-1829. (American Physical Society)
      A self-consistent real-space multiple-scattering (RSMS) approach for calcns. of x-ray-absorption near-edge structure (XANES) is presented and implemented in an ab initio code applicable to arbitrary aperiodic or periodic systems. This approach yields a quant. interpretation of XANES based on simultaneous, SCF calcns. of local electronic structure and x-ray absorption spectra, which include full multiple scattering from atoms within a small cluster and the contributions of high-order MS from scatterers outside that cluster. The code includes a SCF est. of the Fermi energy and an account of orbital occupancy and charge transfer. The authors also present a qual., scattering-theoretic interpretation of XANES. Sample applications are presented for cubic BN, UF6, Pu hydrates, and distorted PbTiO3. Limitations and various extensions are also discussed.
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      Carcelli, M.; Tegoni, M.; Bartoli, J.; Marzano, C.; Pelosi, G.; Salvalaio, M.; Rogolino, D.; Gandin, V. In vitro and in vivo anticancer activity of tridentate thiosemicarbazone copper complexes: Unravelling an unexplored pharmacological target. Eur. J. Med. Chem. 2020, 194, 112266,  DOI: 10.1016/j.ejmech.2020.112266
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      In vitro and in vivo anticancer activity of tridentate thiosemicarbazone copper complexes: Unravelling an unexplored pharmacological target
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      European Journal of Medicinal Chemistry (2020), 194 (), 112266CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
      Certain metal complexes can have a great antitumor activity, as the use of cisplatin in therapy was demonstrating for the past fifty years. Copper complexes, in particular, have attracted much attention as an example of anticancer compds. based on an endogenous metal. The authors present the synthesis and the activity of copper(II) complexes with variously substituted salicylaldehyde thiosemicarbazone ligands. The in vitro activity of both ligands and copper complexes was assessed on a panel of cell lines (HCT-15, LoVo and LoVo oxaliplatin resistant colon carcinoma, A375 melanoma, BxPC3 and PSN1 pancreatic adenocarcinoma, BCPAP thyroid carcinoma, 2008 ovarian carcinoma, HEK293 nontransformed embryonic kidney), highlighting remarkable activity of the metal complexes, in some cases in the low nanomolar range. The copper(II) complexes were also screened, with good results, against 3-dimensional spheroids of colon (HCT-15) and pancreatic (PSN1) cancer cells. Detailed investigations on the mechanism of action of the copper(II) complexes are also reported: they are able to potently inhibit Protein Disulfide Isomerase, a copper-binding protein, that is recently emerging as a new therapeutic target for cancer treatment. Good preliminary results obtained in C57BL mice indicate that this series of metal-based compds. could be a very promising weapon in the fight against cancer.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXmsVSnsbc%253D&md5=9d9343877d2df2fa42e9a9972497a7ef
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      Rigobello, M. P.; Folda, A.; Citta, A.; Scutari, G.; Gandin, V.; Fernandes, A. P.; Rundlöf, A.-K.; Marzano, C.; Björnstedt, M.; Bindoli, A. Interaction of selenite and tellurite with thiol-dependent redox enzymes: Kinetics and mitochondrial implications. Free Radical Biol. Med. 2011, 50, 1620– 1629,  DOI: 10.1016/j.freeradbiomed.2011.03.006
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      Interaction of selenite and tellurite with thiol-dependent redox enzymes: Kinetics and mitochondrial implications
      Rigobello, Maria Pia; Folda, Alessandra; Citta, Anna; Scutari, Guido; Gandin, Valentina; Fernandes, Aristi Potamitou; Rundloef, Anna-Klara; Marzano, Cristina; Bjoernstedt, Mikael; Bindoli, Alberto
      Free Radical Biology & Medicine (2011), 50 (11), 1620-1629CODEN: FRBMEH; ISSN:0891-5849. (Elsevier B.V.)
      The interactions of selenite and tellurite with cytosolic and mitochondrial thioredoxin reductases (TrxR1 and TrxR2) and glutathione reductases (GR) from yeast and mammalian sources were explored. Both TrxR1 and TrxR2 act as selenite and tellurite reductases. Kinetic treatment shows that selenite has a greater affinity than tellurite with both TrxR1 and TrxR2. Considering both k cat and K m, selenite shows a better catalytic efficiency than tellurite with TrxR1, whereas with TrxR2, the catalytic efficiency is similar for both chalcogens. Tellurite is a good substrate for GR, whereas selenite is almost completely ineffective. Selenite or tellurite det. a large mitochondrial permeability transition assocd. with thiol group oxidn. However, with increasing concns. of both chalcogens, only about 25% of total thiols are oxidized. In isolated mitochondria, selenite or tellurite per se does not stimulate H2O2 prodn., which, however, is increased by the presence of auranofin. They also det. a large oxidn. of mitochondrial pyridine nucleotides. In ovarian cancer cells both chalcogens decrease the mitochondrial membrane potential. These results indicate that selenite and tellurite, interacting with the thiol-dependent enzymes, alter the balance connecting pyridine nucleotides and thiol redox state, consequently leading to mitochondrial and cellular alterations essentially referable to a disulfide stress.
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    • EXAFS data analysis details; XPS data analysis results: BE, FWHM, atomic percents, and proposed assignments; XPS Cu 2p spectra of Cu(II) complex 10 (A) and Cu(I) complex 15 (B); and stability studies, where all complexes were dissolved at 50 μM in 0.5% DMSO/RPMI medium and UV–visible spectra were recorded at t = 0 min and t = 1440 min = 24 h (PDF)


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