A Strategy to Conjugate Bioactive Fragments to Cytotoxic Diiron Bis(cyclopentadienyl) Complexes

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This article references 43 other publications.

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   The platinum-based drugs cisplatin, carboplatin and oxaliplatin are regularly prescribed in the treatment of cancer and while they are effective, their use is limited by their severe, dose-limiting side effects (also referred to as adverse effects/events). In total, a cancer patient can experience any combination of around 40 specific side effects. The dose-limiting side effect for cisplatin is nephrotoxicity, for carboplatin it is myelosuppression, and for oxaliplatin it is neurotoxicity. Other common side effects include anaphylaxis, cytopenias (including leukopenia and neutropenia, thrombocytopenia, and anemia), hepatotoxicity, ototoxicity, cardiotoxicity, nausea and vomiting, diarrhea, mucositis, stomatitis, pain, alopecia, anorexia, cachexia, and asthenia. The side effects may require patients to be prescribed dose redns. in their platinum drugs of between 25 and 100%. Furthermore, patients require extensive monitoring of their biochemistries, kidney and liver function, and depending on the drug, hearing tests. Finally, patients are commonly co-prescribed addnl. non-chemotherapy based drugs to treat the side effects which can include antiemetics, antibiotics and myeloid growth factors, mannitol, propafenone, saline hyperhydration, magnesium supplements, monoclonal antibody cytokine blockers and antioxidants.

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   A review. Cisplatin is one of the most potent antitumor agents known, displaying clin. activity against a wide variety of solid tumors. Its cytotoxic mode of action is mediated by its interaction with DNA to form DNA adducts, primarily intrastrand crosslink adducts, which activate several signal transduction pathways, including those involving ATR, p53, p73, and MAPK, and culminate in the activation of apoptosis. DNA damage-mediated apoptotic signals, however, can be attenuated, and the resistance that ensues is a major limitation of cisplatin-based chemotherapy. The mechanisms responsible for cisplatin resistance are several, and contribute to the multifactorial nature of the problem. Resistance mechanisms that limit the extent of DNA damage include reduced drug uptake, increased drug inactivation, and increased DNA adduct repair. Origins of these pharmacol.-based mechanisms, however, are at the mol. level. Mechanisms that inhibit propagation of the DNA damage signal to the apoptotic machinery include loss of damage recognition, overexpression of HER-2/neu, activation of the PI3-K/Akt (also known as PI3-K/PKB) pathway, loss of p53 function, overexpression of antiapoptotic bcl-2, and interference in caspase activation. The mol. signature defining the resistant phenotype varies between tumors, and the no. of resistance mechanisms activated in response to selection pressures dictates the overall extent of cisplatin resistance.

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   Endocrine-Related Cancer (2015), 22 (4), R219-R233CODEN: ERCAE9; ISSN:1351-0088. (BioScientifica Ltd.)

   The year 2015 marks the 50th anniversary since the discovery of the anticancer potential of cisplatin and it remains just as useful now as it did back then, esp. for the treatment of some endocrine-related cancers like ovarian and testicular carcinomas. Since its discovery, five other platin drugs have received approval in various countries. While several new platin drugs are in preclin. development, in the last decade only two new platin drugs have entered clin. trials, LA-12 and dicycloplatin, reflecting a shift in research focus from new drug design to improved formulations of already approved platin drugs. These formulations include their encapsulation with macrocycles to slow and prevent their degrdn. by proteins and peptides; their attachment to nanoparticles to passively target solid tumors through the enhanced permeability and retention effect and their coordination to important nutrients, proteins, antibodies and aptamers for active tumor targeting. These formulation methods have all shown potential but none have yet yielded a new marketable medicine contg. a platin drug. The reasons for this are problems of consistent drug loading, controlling the location and timing of drug release and the inherent toxicity of some of the drug delivery vehicles. In addn. to drug delivery, functional genomics is now playing an increasing role in predicting patients' responses to platin chemotherapy and their likelihood of experiencing severe side effects.
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   A review. From their early successes in medicine, organometallic compds. continue to attract interest as potential chemotherapeutics to treat a range of diseases. Here, we show from recent literature selected largely from the last two years that organometallics offer unique opportunities in medicine and, increasingly, a mechanistic-based approach is applied to their development, which has not always been the case.

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   Advances in the design of organometallic anticancer complexes

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   Organometallic complexes contg. ligands such as CO, carbenes, alkyls, phenyls, π-bound alkynes, alkenes, cyclopentadienyls and arenes possess properties which have often been exploited in areas such as catalysis and materials chem. They also offer opportunities for the design of new drugs with novel mechanisms of action. Here we focus on anticancer drugs which might complement successful platinum drugs in the clinic by widening the spectrum of activity, reducing side-effects and combating resistance. The early clin. trials of titanocene dichloride highlighted the need to understand the aq. soln. chem. of organometallic complexes and to identify their target sites in cancer cells. More recently organometallic Cp complexes of Fe(II), Rh(III) and Ir(III), and arene complexes of Ru(II) and Os(II), have been shown to target the redox balance in cancer cells, in contrast to DNA which is the target of cisplatin and related platinum drugs. The activity of both catalytic and photoactive organometallic compds. is being explored. Target recognition and activity are highly dependent not only on the metal and its oxidn. state, but also the other coordinated ligands, the coordination no. and geometry. In general, organometallic complexes are 'pro-drugs' which undergo activation in vivo (by ligand exchange or redox reactions), and the ligands themselves may be active components of the drug. A major challenge is to elucidate the chem. of organometallic complexes directly in cells. The design of organometallic complexes for therapeutic and diagnostic applications in cancer and other areas of medicine present new and exciting research opportunities.

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   Metallodrugs offer potential for unique mechanism of drug action based on the choice of the metal, its oxidn. state, the types and no. of coordinated ligands and the coordination geometry. This review illustrates notable recent progress in the field of medicinal bioinorg. chem. as many new approaches to the design of innovative metal-based anticancer drugs are emerging. Current research addressing the problems assocd. with platinum drugs has focused on other metal-based therapeutics that have different modes of action and on prodrug and targeting strategies in an effort to diminish the side-effects of cisplatin chemotherapy. Examples of metal compds. and chelating agents currently in clin. use, clin. trials or preclin. development are highlighted.

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   Anticancer metallodrugs based on ruthenium and osmium are among the most investigated and advanced non-platinum metallodrugs. Inorg. drug discovery with these agents has undergone considerable advances over the past two decades and has currently two representatives in active clin. trials. As many ruthenium and osmium metallodrugs are prodrugs, a key question to be addressed is how the mol. reactivity of such metal-based therapeutics dictates the selectivity and the type of interaction with mol. targets. Within this frame, this review introduces the field by the examples of the most advanced ruthenium lead structures. Then, global structure-activity relationships are discussed for ruthenium and osmium metallodrugs with respect to in vitro antiproliferative/cytotoxic activity and in vivo tumor-inhibiting properties, as well as pharmacokinetics. Detg. and validating global mechanisms of action and mol. targets are still major current challenges. Moreover, significant efforts must be invested in screening in vivo tumor models that mimic human pathophysiol. to increase the predictability for successful preclin. and clin. development of ruthenium and osmium metallodrugs.

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   Recent advances in gold-NHC complexes with biological properties

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   Chemical Society Reviews (2019), 48 (2), 447-462CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)

   This tutorial review covers the recent advances made in the study of gold complexes contg. N-heterocyclic carbene ligands with biol. properties. The great stability, ease of modulation of the electronic properties and excellent σ-donating capacity displayed by NHCs allow gold-NHC derivs. to reach high stability in biol. media and relatively good internalization into cells and for that they have emerged as excellent potential chemotherapeutics. The new gold-NHC derivs. show superior anticancer activity compared to other stds. such as Cisplatin or Auranofin. In addn., the application of gold-NHC complexes in the treatment of other human diseases as antibacterial, antioxidant and antiparasitic agents is reviewed for the first time.
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   (a) Jaouen, G.; Vessieres, A.; Top, S. Ferrocifen type anti cancer drugs. Chem. Soc. Rev. 2015, 44, 8802– 8817,  DOI: 10.1039/C5CS00486A

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   Ferrocifen type anti cancer drugs

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   Chemical Society Reviews (2015), 44 (24), 8802-8817CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)

   Despite current developments in therapeutics focusing on biotechnol.-oriented species, the unflagging utility of small mols. or peptides in medicine is still producing strong results. In 2014 for example, of the 41 new medicines authorized for sale, 33 belonged to the category of small mols., while in 2013 they represented 24 of 27, according to the FDA. This can be explained as the result of recent forays into new or long-neglected areas of chem. Medicinal organometallic chem. can provide us with an antimalarial against resistant parasitic strains, as attested by the phase II clin. development of ferroquine, with a new framework for conceptual advances based on three-dimensional space-filling, and with redox or indeed catalytic intracellular properties. In this context, bioferrocene species with antiproliferative potential have for several years been the subject of sustained effort, based on some initial successes and on the nature of ferrocene as a stable arom., with low toxicity, low cost, and possessing reversible redox properties. We show here the different antitumoral approaches offered by ferrocifen derivs., originally simple derivs. of tamoxifen, which over the course of their development have proved to possess remarkable structural and mechanistic diversity. These entities act via various targets, some of which have been identified, that are triggered according to the concn. of the products. They also act according to the nature of the cancer cells and their functionality, by mechanistic pathways that can operate either synergistically or not, in successive, concomitant or sequential ways, depending for example on newly identified signaling pathways inducing senescence or apoptosis. Here we present a first attempt to rationalize the behavior of these entities with various anticancer targets.

   (b) Patra, M.; Gasser, G. The medicinal chemistry of ferrocene and its derivatives. Nat. Chem. Rev. 2017, 1, 0066,  DOI: 10.1038/s41570-017-0066

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   The medicinal chemistry of ferrocene and its derivatives

   Patra, Malay; Gasser, Gilles

   Nature Reviews Chemistry (2017), 1 (9), 0066CODEN: NRCAF7; ISSN:2397-3358. (Nature Research)

   A review. Ferrocene derivs. have attracted significant interest as anticancer, antibacterial, antifungal and antiparasitic drug candidates. Discovered in the 1990s, the two most prominent derivs., ferroquine and ferrocifen, have since been studied extensively for the treatment of malaria and cancer, resp. The ferrocenyl moiety in these two compds. participates in important metal-specific modes of action that contribute to the overall therapeutic efficacy of the mols. Although ferroquine is currently in phase II clin. trials and ferrocifen is in preclin. evaluation, no other ferrocene deriv. - in fact, no other non-radioactive organometallic compd. of any kind - has advanced into clin. trials. This Perspective delineates strategies for the systematic incorporation of ferrocenyl groups into known drugs or drug candidates, with a view to finding new drug leads. In addn., we provide a crit. evaluation of the difficulties assocd. with obtaining the clin. approval that would enable ferrocene-contg. mols. to transition from being synthetic curiosities to effective drugs.
5. 5

   (a) Wang, Y.; Dansette, P. M.; Pigeon, P.; Top, S.; McGlinchey, M. J.; Mansuy, D.; Jaouen, G. A new generation of ferrociphenols leads to a great diversity of reactive metabolites, and exhibits remarkable antiproliferative properties. Chem. Sci. 2018, 9, 70– 78,  DOI: 10.1039/C7SC04213B

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   A new generation of ferrociphenols leads to a great diversity of reactive metabolites, and exhibits remarkable antiproliferative properties

   Wang, Yong; Dansette, Patrick M.; Pigeon, Pascal; Top, Siden; McGlinchey, Michael J.; Mansuy, Daniel; Jaouen, Gerard

   Chemical Science (2018), 9 (1), 70-78CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)

   Organometallic compds. bearing the redox motif [ferrocenyl-ene-phenol] have very promising antiproliferative properties which have been further improved by incorporating pertinent substituents able to engender new mechanisms. Here we show that novel ferrociphenols bearing a hydroxypropyl chain exhibit strong antiproliferative effects, in most cases much better than those of cisplatin, tamoxifen, or of previously described ferrociphenols devoid of this terminal OH. This is illustrated, in the case of one of these compds., by its IC50 values of 110 nM for MDA-MB-231 triple neg. breast cancer cells and of 300 nM for cisplatin-resistant A2780cisR human ovarian cancer cells, and by its GI50 values lower than 100 nM towards a series of melanoma and renal cancer cell lines of the NCI-60 panel. Interestingly, oxidative metab. of these hydroxypropyl-ferrociphenols yields two kinds of quinone methides (QMs) that readily react with various nucleophiles, such as glutathione, to give 1,6- and 1,8-adducts. Protonation of these quinone methides generates numerous reactive metabolites leading eventually to many rearrangement and cleavage products. This unprecedented and fully characterized metabolic profile involving a wide range of electrophilic metabolites that should react with cell macromols. may be linked to the remarkable profile of antiproliferative activities of this new series. Indeed, the great diversity of unexpected reactive metabolites found upon oxidn. will allow them to adapt to various situations present in the cancer cell. These data initiate a novel strategy for the rational design of anticancer mols., thus opening the way to new organometallic potent anticancer drug candidates for the treatment of chemoresistant cancers.

   (b) Leonidova, A.; Anstaett, P.; Pierroz, V.; Mari, C.; Spingler, B.; Ferrari, S.; Gasser, G. Induction of Cytotoxicity through Photorelease of Aminoferrocene. Inorg. Chem. 2015, 54, 9740– 9748,  DOI: 10.1021/acs.inorgchem.5b01332

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   5b

   Induction of Cytotoxicity through Photorelease of Aminoferrocene

   Leonidova, Anna; Anstaett, Philipp; Pierroz, Vanessa; Mari, Cristina; Spingler, Bernhard; Ferrari, Stefano; Gasser, Gilles

   Inorganic Chemistry (2015), 54 (20), 9740-9748CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)

   Reactive oxygen species (ROS)-activated aminoferrocene-based anticancer prodrug candidates successfully take advantage of intrinsically high amts. of ROS in tumor tissues. Interestingly, the ROS-initiated activation of these prodrug candidates leads to formation of unstable aminoferrocene (Fc-NH2) derivs., which decay to iron ions. The latter catalytically increases ROS concn. to a lethal level. In this work, we prepd. light-controlled aminoferrocene prodrug candidates by derivatizing Fc-NH2 with an o-nitrophenyl and an o-nitrobiphenyl photolabile protecting group (PLPG), resp., and by further conjugation to a mitochondria localization signal (MLS) peptide (Cys-D-Arg-Phe-Lys-NH2). The resulting bioconjugates were found to be more stable and less cytotoxic, in the dark, toward human promyelocytic leukemia cells (HL-60) compared to Fc-NH2. Upon light irradn. at 355 nm, both conjugates released Fc-NH2, albeit with very different photolysis quantum yields. The o-nitrobiphenyl photocage was in fact several orders of magnitude more efficient than the o-nitrophenyl photocage in releasing Fc-NH2. This difference was reflected by the light irradn. expts. on the HL-60 cell line, in which aminoferrocene conjugated with the o-nitrobiphenyl cage and the MLS displayed the highest phototoxicity index (2.5 ± 0.4) of all the compds. tested. The iron release assays confirmed the rise in iron ion concns. upon light irradn. of both caged aminoferrocene derivs. Together with the absence of phototoxicity on the nonmalignant hTERT-immortalized retinal pigment epithelial (hTERT RPE-1) cell line, these results indicate catalytic generation of ROS as possible mode of action.

   (c) Ocasio, C. A.; Sansook, S.; Jones, R.; Roberts, J. M.; Scott, T. G.; Tsoureas, N.; Coxhead, P.; Guille, M.; Tizzard, G. J.; Coles, S. J.; Hochegger, H.; Bradner, J. E.; Spencer, J. Pojamide: An HDAC3-Selective Ferrocene Analogue with Remarkably Enhanced Redox-Triggered Ferrocenium Activity in Cells. Organometallics 2017, 36, 3276– 3283,  DOI: 10.1021/acs.organomet.7b00437

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   5c

   Pojamide: An HDAC3-Selective Ferrocene Analogue with Remarkably Enhanced Redox-Triggered Ferrocenium Activity in Cells

   Ocasio, Cory A.; Sansook, Supojjanee; Jones, Rhiannon; Roberts, Justin M.; Scott, Thomas G.; Tsoureas, Nikolaos; Coxhead, Peter; Guille, Matthew; Tizzard, Graham J.; Coles, Simon J.; Hochegger, Helfrid; Bradner, James E.; Spencer, John

   Organometallics (2017), 36 (17), 3276-3283CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)

   A ferrocene contg. ortho-aminoanilide, N1-(2-aminophenyl)-N8-ferrocenyloctanediamide, 2b (Pojamide) displayed nanomolar potency vs. HDAC3. Compared to RGFP966, a potent and selective HDAC3 inhibitor, Pojamide displayed superior activity in HCT116 colorectal cancer cell invasion assays; however, TCH106 and Romidepsin, potent HDAC1 inhibitors, outperformed Pojamide in cellular proliferation and colony formation assays. Together, these data suggest that HDAC 1 and 3 inhibition is desirable to achieve max. anticancer benefits. Addnl., the authors explored Pojamide-induced redox-pharmacol. Indeed, treating HCT116 cells with Pojamide, SNP (Na nitroprusside) and glutathione (GSH) led to greatly enhanced cytotoxicity and DNA damage attributed to activation to an Fe(III) species.
6. 6

   (a) Pilon, A.; Gírio, P.; Nogueira, G.; Avecilla, F.; Adams, H.; Lorenzo, J.; Garcia, M. H.; Valente, A. New iron cyclopentadienyl complexes bearing different phosphane co-ligands: Structural factors vs. cytotoxicity. J. Organomet. Chem. 2017, 852, 34– 42,  DOI: 10.1016/j.jorganchem.2017.10.004

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   6a

   New iron cyclopentadienyl complexes bearing different phosphane co-ligands: Structural factors vs. cytotoxicity

   Pilon, Adhan; Girio, Patricia; Nogueira, Guilherme; Avecilla, Fernando; Adams, Harry; Lorenzo, Julia; Garcia, M. Helena; Valente, Andreia

   Journal of Organometallic Chemistry (2017), 852 (), 34-42CODEN: JORCAI; ISSN:0022-328X. (Elsevier B.V.)

   A new family of piano stool iron-cyclopentadienyl compds. bearing different phosphine co-ligands has been synthesized. All the compds., with the general structure [Fe(Cp)(CO)(PR3)(L)]n (PR3 = triphenylphosphine, 4-(diphenylphosphino) benzoic acid or tris(4-fluorophenyl)phosphine; when L = I, n = 0; when L = 4-aminobenzonitrile, n = +1) were fully characterized by the usual anal. and spectroscopic techniques. Interestingly, compd. [Fe(Cp)(CO)(PPh3)I] 1 crystallizes in the orthorhombic space group P212121 and its crystal packing only contains one enantiomer, while compd. [Fe(η5-Cp)(CO)(P(Ph-p-F)3)I] 3 crystallizes in the centrosym. space group Pbca presenting an important disorder in the structure, probably due to the presence of the two enantiomers in the crystal packing. All the compds. presented adequate stability in aq. soln. and they were tested against cervical HeLa human cancer cells. The cationic complexes bearing triphenylphosphine (4) or tris(4-fluorophenyl)phosphine (6) were found to be highly cytotoxic, causing cell death by apoptosis. The results point out that the electronic features of the new compds. might be related to their cytotoxic activity.

   (b) Florindo, P. R.; Pereira, D. M.; Borralho, P. M.; Rodrigues, C. M. P.; Piedade, M. F. M.; Fernandes, A. C. Cyclopentadienyl–Ruthenium(II) and Iron(II) Organometallic Compounds with Carbohydrate Derivative Ligands as Good Colorectal Anticancer Agents. J. Med. Chem. 2015, 58, 4339– 4347,  DOI: 10.1021/acs.jmedchem.5b00403

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   6b

   Cyclopentadienyl-Ruthenium(II) and Iron(II) Organometallic Compounds with Carbohydrate Derivative Ligands as Good Colorectal Anticancer Agents

   Florindo, Pedro R.; Pereira, Diane M.; Borralho, Pedro M.; Rodrigues, Cecilia M. P.; Piedade, M. F. M.; Fernandes, Ana C.

   Journal of Medicinal Chemistry (2015), 58 (10), 4339-4347CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

   New ruthenium(II) and iron(II) organometallic compds. of general formula [(η5-C5H5)M(PP)Lc][PF6], bearing carbohydrate deriv. ligands (Lc), were prepd. and fully characterized and the crystal structures of five of those compds. were detd. by X-ray diffraction studies. Cell viability of colon cancer HCT116 cell line was detd. for a total of 23 organometallic compds. and SAR's data anal. within this library showed an interesting dependency of the cytotoxic activity on the carbohydrate moiety, linker, phosphine coligands, and metal center. More importantly, two ruthenium compds. matched oxaliplatin IC50 (0.45 μM), the std. metallodrug used in CC chemotherapeutics, and our leading ruthenium compd. was shown to be significantly more cytotoxic than oxaliplatin to HCT116 cells, triggering higher levels of caspase-3 and -7 activity and apoptosis in a dose-dependent manner.

   (c) Herry, B.; Batchelor, L. K.; Roufosse, B.; Romano, D.; Baumgartner, J.; Borzova, M.; Reifenstahl, T.; Collins, T.; Benamrane, A.; Weggelaar, J.; Correia, M. C.; Dyson, P. J.; Blom, B. Heterobimetallic Ru(μ-dppm)Fe and homobimetallic Ru(μ-dppm)Ru complexes as potential anti-cancer agents. J. Organomet. Chem. 2019, 901, 120934,  DOI: 10.1016/j.jorganchem.2019.120934

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   6c

   Heterobimetallic Ru(μ-dppm)Fe and homobimetallic Ru(μ-dppm)Ru complexes as potential anti-cancer agents

   Herry, Brian; Batchelor, Lucinda K.; Roufosse, Basile; Romano, Dario; Baumgartner, Judith; Borzova, Marina; Reifenstahl, Tim; Collins, Thomas; Benamrane, Amal; Weggelaar, Jordana; Correia, Marie C.; Dyson, Paul J.; Blom, Burgert

   Journal of Organometallic Chemistry (2019), 901 (), 120934CODEN: JORCAI; ISSN:0022-328X. (Elsevier B.V.)

   Two heterobimetallic μ-dppm bridged Fe,Ru complexes, [(η6-Arene)RuCl2(μ-dppm)Fe(CO)I(η5-C5H5)] (Ar = C6H6 (1) and p-cymene (2), dppm = 1,1-bis(diphenylphosphino)methane) were obtained in a facile reaction between [Fe(η5-C5H5)I(CO)(κ1-dppm)] (5) and the corresponding [(η6-Arene)RuCl2]2 complexes by dimer cleavage, mediated by the pendant -PPh2 in 5. The homodinuclear Ru,Ru complex, [(η6-C6H6)RuCl2(μ-dppm)RuCl2(η6-C6H6)] (3), was also isolated in a straightforward fashion upon reaction of [(η6-C6H6)RuCl2(κ1-dppm)] (4) with [(η6-C6H6)RuCl2]2. All complexes were fully characterized by multinuclear (1H, 13C{1H}, 31P{1H}) NMR, UV-Vis, IR spectroscopy and HRMS (ESI), and addnl. complex 3 was characterized by single crystal X-ray diffraction. D. functional theory (DFT) calcns. (Level of theory B3LYP, basis set for H, C, P, O, N and Cl is 6-31 + G(d,p) and for Ru,Fe DGDZVP) of 1, 2 and 3 are also reported. Complexes 1 and 2 feature HOMOs and LUMOs delocalized over the iron-centered terminus of the bimetallic complexes. The cytotoxicity of 1-5 were evaluated on A2780 and A2780cisR (Human ovarian carcinoma) cell lines and the HEK293 (Human embryonic kidney) cell line. The complexes contg. iron are more cytotoxic than cisplatin in the A2780 cells and significantly more active in the A2780cisR cell line and exhibit some selectivity towards the cancer cells. The dinuclear Ru,Ru complex 3 and the mononuclear complex 4 exhibit moderate activity on A2780 and A2780cisR cells also with some cancer cell selectivity. This study hence reveals the potential of Fe,Ru complexes as potent cytotoxic agents.
7. 7

   Agonigi, G.; Biancalana, L.; Lupo, M. G.; Montopoli, M.; Ferri, N.; Zacchini, S.; Binacchi, F.; Biver, T.; Campanella, B.; Pampaloni, G.; Zanotti, V.; Marchetti, F. Exploring the Anticancer Potential of Diiron Bis-cyclopentadienyl Complexes with Bridging Hydrocarbyl Ligands: Behavior in Aqueous Media and In Vitro Cytotoxicity. Organometallics 2020, 39, 645– 657,  DOI: 10.1021/acs.organomet.9b00681

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   7

   Exploring the Anticancer Potential of Diiron Bis-cyclopentadienyl Complexes with Bridging Hydrocarbyl Ligands: Behavior in Aqueous Media and In Vitro Cytotoxicity

   Agonigi, Gabriele; Biancalana, Lorenzo; Lupo, Maria Giovanna; Montopoli, Monica; Ferri, Nicola; Zacchini, Stefano; Binacchi, Francesca; Biver, Tarita; Campanella, Beatrice; Pampaloni, Guido; Zanotti, Valerio; Marchetti, Fabio

   Organometallics (2020), 39 (5), 645-657CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)

   A series of diiron complexes based on the [Fe2Cp2(CO)x] skeleton (Cp = η5-C5H5, x = 2, 3; η4-C5H5Ph in place of one Cp in one case) and contg. different bridging hydrocarbyl ligands (aminocarbyne, thiocarbyne, allenyl) were preliminarily investigated for their anticancer potential. The water soly., stability in water and in the presence of a cell culture medium, and octanol/water partition coeff. were evaluated by spectroscopic techniques. The cytotoxicity was assessed in vitro toward the human ovarian carcinoma cell line A2780, the human triple neg. breast cancer cell line MDA-MB-231, and the human vascular smooth muscle cell line SMC. Some aminocarbyne complexes exhibited a potent cytotoxicity, with IC50 values in the low micromolar/nanomolar range, and a strong selectivity for the A2780 cells in comparison to the SMC cell line. Several expts. were carried out in order to give insight into the mode of action of selected compds., including an assessment of catalytic NADH oxidn. and ROS prodn. and studies of binding with DNA and with a model protein.
8. 8

   See for instance:

   (a) Ritleng, V.; Chetcuti, M. J. Hydrocarbyl Ligand Transformations on Heterobimetallic Complexes. Chem. Rev. 2007, 107, 797– 858,  DOI: 10.1021/cr940270y

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   Hydrocarbyl Ligand Transformations on Heterobimetallic Complexes

   Ritleng, Vincent; Chetcuti, Michael J.

   Chemical Reviews (Washington, DC, United States) (2007), 107 (3), 797-858CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)

   A review of hydrocarbyl ligand transformations, e.g., carbon-carbon and carbon-hydrogen bond formations and bond cleavage and rearrangement reactions on preformed heterobimetallic frameworks.

   (b) Adams, R. D.; Captain, B. Bimetallic cluster complexes: Synthesis, structures and applications to catalysis. J. Organomet. Chem. 2004, 689, 4521– 4529,  DOI: 10.1016/j.jorganchem.2004.08.001

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   Bimetallic cluster complexes: synthesis, structures and applications to catalysis

   Adams, Richard D.; Captain, Burjor

   Journal of Organometallic Chemistry (2004), 689 (24), 4521-4529CODEN: JORCAI; ISSN:0022-328X. (Elsevier B.V.)

   A review. A brief history of the seminal discoveries in the field of bimetallic cluster complexes with their structures is presented. A review of some recent studies of palladium and platinum-ruthenium cluster complexes is concluded with a discussion of applications of these complexes in the area of homogeneous hydrogenation catalysis of alkynes.

   (c) Patra, S.; Maity, N. Recent advances in (hetero)dimetallic systems towards tandem catalysis. Coord. Chem. Rev. 2021, 434, 213803,  DOI: 10.1016/j.ccr.2021.213803

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   8c

   Recent advances in (hetero)dimetallic systems towards tandem catalysis

   Patra, Srikanta; Maity, Niladri

   Coordination Chemistry Reviews (2021), 434 (), 213803CODEN: CCHRAM; ISSN:0010-8545. (Elsevier B.V.)

   Combining multiple mechanistically distinct reactions in one-pot (tandem reaction) is a fascinating area in catalysis research. The tandem reaction becomes the subject of interest as it offers environmentally benign, green, and sustainable process with high atom economy, minimizing the loss of reagents, consumption of energy and chem. waste generation. Considering the advantages and usefulness of metal catalyzed tandem reaction, the present review focuses on highlighting the use of different metal complexes (monometallic, homodimetallic and mixt. of multiple metal complexes) in conducting tandem reaction. Further, a special emphasis is given to the heterodimetallic systems, considering their usefulness in ease of modification of active centers, elimination of catalytic incompatibility and better activity and selectivity as compared to mono- and homodimetallic systems.

   (d) van Niekerk, A.; Chellan, P.; Mapolie, S. F. Heterometallic Multinuclear Complexes as Anti-Cancer Agents- An Overview of Recent Developments. Eur. J. Inorg. Chem. 2019, 2019, 3432– 3455,  DOI: 10.1002/ejic.201900375

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   8d

   Heterometallic Multinuclear Complexes as Anti-Cancer Agents-An Overview of Recent Developments

   van Niekerk, Annick; Chellan, Prinessa; Mapolie, Selwyn F.

   European Journal of Inorganic Chemistry (2019), 2019 (30), 3432-3455CODEN: EJICFO; ISSN:1434-1948. (Wiley-VCH Verlag GmbH & Co. KGaA)

   This review provides a crit. assessment of the advances made in the development of heterometallic multinuclear complexes as potential chemotherapeutic agents, with the aim of providing a starting point for future investigators. The combination of the classical transition metals (Pt, Ru and Au) with other metal moieties has the potential to result in complexes with improved pharmacokinetic and pharmacodynamic properties. This enables selective targeting of the biol. targets, which offers a possible way of circumventing the issue of drug-resistance. This review catalogues the reported heterometallic multinuclear complexes and comments on possible synergism, stability, structure activity relationships and mechanistic studies. It was found that there remains a large scope for future research, esp. concerning the combination of PtIV and CuI metals with other metals centers.
9. 9

   Selected reviews:

   (a) Mazzoni, R.; Salmi, M.; Zanotti, V. C-C Bond Formation in Diiron Complexes. Chem. - Eur. J. 2012, 18, 10174– 10194,  DOI: 10.1002/chem.201201040

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   9a

   C-C Bond Formation in Diiron Complexes

   Mazzoni, Rita; Salmi, Mauro; Zanotti, Valerio

   Chemistry - A European Journal (2012), 18 (33), 10174-10194CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)

   A review. The growing effort to design new sustainable synthetic methodologies, based on readily available and environmentally friendly transition metals, has boosted research on iron complexes. This review article focuses on C-C bond-forming reactions occurring at bridging ligands in diiron complexes, aimed at evidencing distinctive aspects and advantages assocd. with the presence of two adjacent iron centers. A no. of diiron-mediated C-C-bond-forming reactions reported in the literature, including nucleophilic and electrophilic addns. and insertion and cycloaddn. reactions, have been accumulated over the years, which, together with more recent developments, indicate that diiron complexes might provide promising alternatives to precious metals in the challenging field of metal-promoted C-C bond formation.

   (b) Marchetti, F. Constructing Organometallic Architectures from Aminoalkylidyne Diiron Complexes. Eur. J. Inorg. Chem. 2018, 2018, 3987– 4003,  DOI: 10.1002/ejic.201800659

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   9b

   Constructing Organometallic Architectures from Aminoalkylidyne Diiron Complexes

   Marchetti, Fabio

   European Journal of Inorganic Chemistry (2018), 2018 (36), 3987-4003CODEN: EJICFO; ISSN:1434-1948. (Wiley-VCH Verlag GmbH & Co. KGaA)

   A review. The chem. of diiron complexes has seen a recent renaissance, due to the prominent role played by the element iron in the development of sustainable synthetic processes and the cooperative effects provided by two metal centers working in concert, that is a concept amazingly exploited by nature. Aminoalkylidyne derivs. of [Fe2Cp2(CO)4] are a convenient scaffold to grow org. fragments; in particular, the facile removal of one CO ligand opens the doors to the unconventional assembly of mols./ions, affording unusual structural motifs. In particular, vinyliminium complexes result from carbyne-alkyne coupling and offers the opportunity for a great variety of selective derivatization pathways, including addn. of nucleophiles, access to substituted ferrocenes, deprotonation and redn. processes, and trapping of small mols.

   (c) García, M. E.; García-Vivó, D.; Ramos, A.; Ruiz, M. A. Phosphinidene-bridged binuclear complexes. Coord. Chem. Rev. 2017, 330, 1– 36,  DOI: 10.1016/j.ccr.2016.09.008

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   Phosphinidene-bridged binuclear complexes

   Garcia, M. Esther; Garcia-Vivo, Daniel; Ramos, Alberto; Ruiz, Miguel A.

   Coordination Chemistry Reviews (2017), 330 (), 1-36CODEN: CCHRAM; ISSN:0010-8545. (Elsevier B.V.)

   A review. This article contains a comprehensive review of the work carried out within the last three decades on the synthesis, structural studies and reactivity of the binuclear complexes of transition and lanthanide elements bearing bridging phosphinidene (PR) ligands. The latter are grouped into three different classes according to their geometry and electronic distribution: pyramidal, sym. planar trigonal and asym. planar trigonal. Different reactivity patterns can be then outlined for each of these classes of metal complexes, which differ in many ways from those characterizing the extensively studied chem. behavior of mononuclear phosphinidene complexes.
10. 10

    (a) Ciancaleoni, G.; Zacchini, S.; Zanotti, V.; Marchetti, F. DFT Mechanistic Insights into the Alkyne Insertion Reaction Affording Diiron μ-Vinyliminium Complexes and New Functionalization Pathways. Organometallics 2018, 37, 3718– 3731,  DOI: 10.1021/acs.organomet.8b00448

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    10a

    DFT Mechanistic Insights into the Alkyne Insertion Reaction Affording Diiron μ-Vinyliminium Complexes and New Functionalization Pathways

    Ciancaleoni, Gianluca; Zacchini, Stefano; Zanotti, Valerio; Marchetti, Fabio

    Organometallics (2018), 37 (21), 3718-3731CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)

    Insertion of propyne or 2-butyne into the Fe-carbyne bond belonging to the fragment [Fe2Cp2(CO)(μ-CO){μ-CNMe(R)}]+ (R = Me or Xyl = 2,6-C6H3Me2) was investigated via d. functional theory (DFT), and plausible intermediates were identified along the formation of the vinyliminium complexes [Fe2Cp2(CO)(μ-CO){μ-η1:η3-C(Me)C(R'')CN(Me)(R)}]SO3CF3, [2a-d]+, thus allowing us to explain regio- and stereochem. features. The X-ray structure of [2a]SO3CF3 (R = Me, R'' = H) was detd. by single crystal X-ray diffraction. Novel C-C and C-S bond forming pathways involving the vinyliminium ligand were then explored. Thus, [2b]SO3CF3 (R = Xyl, R'' = H) reacted with cyclopentadiene (or cyclopentene), triphenylphosphonium methylide, and benzyl bromide, in THF in the presence of sodium hydride, resp., to give [Fe2Cp2(CO)(μ-CO){μ-η1:η2-C(Me)C{C(CH)4}CN(Me)(Xyl)}], 3, [Fe2Cp2(CO)(μ-CO){μ-η1:η2-C(Me)C(CH2)CN(Me)(Xyl)}], 4, and [Fe2Cp2(CO)(μ-CO){μ-η1:η3-C(Me)C(CH2Ph)CN(Me)(Xyl)}]Br, [5]Br, in good yields. Unstable complex 4 (detected by IR spectroscopy) readily converted into [2c]SO3CF3 (R = Xyl, R'' = Me) upon HSO3CF3 protonation of the methylide function. [5]Br was obtained as E/Z isomeric mixt., which was then quant. converted into the most stable Z form, by heating in methanol soln. at 50 °C. The reactions of [2c,d]SO3CF3 (R = Me, Xyl, R'' = Me) with PhSSPh/NaH selectively yielded the aminoalkylidyne species [Fe2Cp2(SPh)(CO)(μ-CO){μ-CN(Me)(Xyl)}], 6, and the bis-alkylidene [Fe2Cp2(CO)(μ-CO){μ-η1:η2-C(Me)C(Me)(SPh)CN(Me)2}], 7, resp., probably via the intermediacy of radical compds. 2c,d. The structures of 3-7 and 2c,d were elucidated by DFT calcns., and the isolated products were characterized by anal. and spectroscopic methods.

    (b) Albano, V. G.; Busetto, L.; Marchetti, F.; Monari, M.; Zacchini, S.; Zanotti, V. Diiron μ-Vinyliminium Complexes from Acetylene Insertion into a Metal–Aminocarbyne Bond. Organometallics 2003, 22, 1326– 1331,  DOI: 10.1021/om020923y

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    10b

    Diiron μ-Vinyliminium Complexes from Acetylene Insertion into a Metal-Aminocarbyne Bond

    Albano, Vincenzo G.; Busetto, Luigi; Marchetti, Fabio; Monari, Magda; Zacchini, Stefano; Zanotti, Valerio

    Organometallics (2003), 22 (6), 1326-1331CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)

    The complexes [Fe2{μ-CN(Me)(R)}(μ-CO)(CO)(NCMe)(Cp)2][SO3CF3] (R = Xyl, 1a; R = Me, 1b; R = CH2Ph, 1c; Xyl = 2,6-Me2C6H3), contg. a labile NCMe ligand, react under mild conditions with a variety of terminal alkynes HC≡CR' (R'= SiMe3, Me, Bun, Tol, Ph, H; Tol = 4-MeC6H4) to give the bridging vinyliminium complexes [Fe2{μ-σ:η3-C(R'):CHC:N(Me)(R)}(μ-CO)(CO)(Cp)2][SO3CF3] (R = Xyl, R' = SiMe3, 2a; R = Me, R' = SiMe3, 2b; R = CH2Ph, R' = SiMe3, 2c; R = Xyl, R' = Me, 3a; R = R' = Me, 3b; R = Xyl, R' = Bun, 4; R = Xyl, R' = Tol, 5a; R = Me, R' = Tol, 5b; R = CH2Ph, R' = Tol, 5c; R = Xyl, R' = Ph, 6; R = Xyl, R' = H, 7). Insertion of the alkyne into the metal-carbyne carbon bond is regiospecific, resulting only in the product contg. the R' group on the carbon bound to Fe. Similarly, insertion of the disubstituted alkynes R'C≡CR' (R' = Me, Et) affords the analogous compds. [Fe2{μ-σ:η3-C(R'):C(R')C:N(Me)(R)}(μ-CO)(CO)(Cp)2][SO3CF3] (R = Xyl, R' = Me, 8a; R = R'= Me, 8b; R = CH2Ph, R' = Me, 8c; R = Xyl, R' = Et, 9a; R = Me, R' = Et, 9b). The mol. structure of complex 2a has been elucidated by an x-ray diffraction study.
11. 11

    Rocco, D.; Batchelor, L. K.; Agonigi, G.; Braccini, S.; Chiellini, F.; Schoch, S.; Biver, T.; Funaioli, T.; Zacchini, S.; Biancalana, L.; Ruggeri, M.; Pampaloni, G.; Dyson, P. J.; Marchetti, F. Anticancer Potential of Diiron Vinyliminium Complexes. Chem. - Eur. J. 2019, 25, 14801– 14816,  DOI: 10.1002/chem.201902885

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    11

    Anticancer potential of diiron vinyliminium complexes

    Rocco, Dalila; Batchelor, Lucinda K.; Agonigi, Gabriele; Braccini, Simona; Chiellini, Federica; Schoch, Silvia; Biver, Tarita; Funaioli, Tiziana; Zacchini, Stefano; Biancalana, Lorenzo; Ruggeri, Marina; Pampaloni, Guido; Dyson, Paul J.; Marchetti, Fabio

    Chemistry - A European Journal (2019), 25 (65), 14801-14816CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)

    Although ferrocene derivs. have attracted considerable attention as possible anticancer agents, the medicinal potential of diiron complexes has remained largely unexplored. Herein, we describe the straightforward multigram-scale synthesis and the antiproliferative activity of a series of diiron cyclopentadienyl complexes contg. bridging vinyliminium ligands. IC50 values in the low-to-mid micromolar range were detd. against cisplatin sensitive and resistant human ovarian carcinoma (A2780 and A2780cisR) cell lines. Notable selectivity towards the cancerous cells lines compared to the non-tumoral human embryonic kidney (HEK-293) cell line was obsd. for selected compds. The activity seems to be multimodal, involving reactive oxygen species (ROS) generation and, in some cases, a fragmentation process to afford monoiron derivs. The large structural variability, amphiphilic character and good stability in aq. media of the diiron vinyliminium complexes provide favorable properties compared to other widely studied classes of iron-based anticancer candidates.
12. 12

    Rocco, D.; Busto, N.; Pérez-Arnaiz, C.; Biancalana, L.; Zacchini, S.; Pampaloni, G.; Garcia, B.; Marchetti, F. Antiproliferative and bactericidal activity of diiron and monoiron cyclopentadienyl carbonyl complexes comprising a vinyl-aminoalkylidene unit. Appl. Organomet. Chem. 2020, 34, e5923  DOI: 10.1002/aoc.5923

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    12

    Antiproliferative and bactericidal activity of diiron and monoiron cyclopentadienyl carbonyl complexes comprising a vinyl-aminoalkylidene unit

    Rocco, Dalila; Busto, Natalia; Perez-Arnaiz, Cristina; Biancalana, Lorenzo; Zacchini, Stefano; Pampaloni, Guido; Garcia, Begona; Marchetti, Fabio

    Applied Organometallic Chemistry (2020), 34 (11), e5923CODEN: AOCHEX; ISSN:0268-2605. (John Wiley & Sons Ltd.)

    A series of diiron complexes with two cyclopentadienyls, two carbonyls, and one bridging vinyl-aminoalkylidene as ligands, [3a-h]CF3SO3 and [4a-d]CF3SO3, was synthesized in 66-94% yields from diiron μ-aminocarbyne precursors. The subsequent reactions with pyrrolidine led to selective fragmentation to aminoalkylidene-ferracyclopentenone derivs. (5a-h and 6a-c) in 30-84% yields. The compds. were characterized by elemental anal., Fourier transform IR and NMR spectroscopy, and by single crystal X-ray diffraction in three cases. The stability in aq. media relevant to biol. trials, the carbon monoxide release, and the catalytic activity in NADH oxidn. were evaluated for selected compds. by NMR spectroscopy and gas chromatog. The in vitro antiproliferative activity of the compds. was detd. towards cancer (A2780, A2780cisR) and noncancer (HEK-293) cell lines. Moreover, the antibacterial activity was tested on Gram-pos. (vancomycin-resistant E. faecium and methicillin-resistant S. aureus) and Gram-neg. strains (A. baumannii and P. aeruginosa).
13. 13

    Agonigi, G.; Batchelor, L. K.; Ferretti, E.; Schoch, S.; Bortoluzzi, M.; Braccini, S.; Chiellini, F.; Biancalana, L.; Zacchini, S.; Pampaloni, G.; Sarkar, B.; Dyson, P. J.; Marchetti, F. Mono-, Di- and Tetra-iron Complexes with Selenium or Sulphur Functionalized Vinyliminium Ligands: Synthesis, Structural Characterization and Antiproliferative Activity. Molecules 2020, 25, 1656,  DOI: 10.3390/molecules25071656

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    13

    Mono-, di- and tetra-iron complexes with selenium or sulphur functionalized vinyliminium ligands: synthesis, structural characterization and antiproliferative activity

    Agonigi, Gabriele; Batchelor, Lucinda K.; Ferretti, Eleonora; Schoch, Silvia; Bortoluzzi, Marco; Braccini, Simona; Chiellini, Federica; Biancalana, Lorenzo; Zacchini, Stefano; Pampaloni, Guido; Sarkar, Biprajit; Dyson, Paul J.; Marchetti, Fabio

    Molecules (2020), 25 (7), 1656CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)

    A series of diiron/tetrairon compds. contg. a S- or a Se-function (2a-d, 4a-d, 5a-b, 6), and the monoiron [FeCp(CO){SeC1(NMe2)C2HC3(Me)}] (3) were prepd. from the diiron μ-vinyliminium precursors [Fe2Cp2(CO)(μ-CO){ μ-η1: η3-C3(R')C1HC1N(Me)(R)}]CF3SO3 (R = R' = Me, 1a; R = 2,6-C6H3Me2 = Xyl, R' = Ph, 6; R = Xyl, R' = CH2OH, 1c), via treatment with S8 or gray selenium. The new compds. were characterized by elemental anal., IR and multinuclear NMR spectroscopy, and structural aspects were further elucidated by DFT calcns. The unprecedented metallacyclic structure of 3 was ascertained by single crystal X-ray diffraction. The air-stable compds. (3, 4a-d, 5a-b, 6) display fair to good stability in aq. media, and thus were assessed for their cytotoxic activity towards A2780, A2780cisR, and HEK-293 cell lines. Cyclic voltammetry, ROS prodn. and NADH oxidn. studies were carried out on selected compds. to give insights into their mode of action.
14. 14

    Schoch, S.; Batchelor, L. K.; Funaioli, T.; Ciancaleoni, G.; Zacchini, S.; Braccini, S.; Chiellini, F.; Biver, T.; Pampaloni, G.; Dyson, P. J.; Marchetti, F. Diiron Complexes with a Bridging Functionalized Allylidene Ligand: Synthesis, Structural Aspects, and Cytotoxicity. Organometallics 2020, 39, 361– 373,  DOI: 10.1021/acs.organomet.9b00813

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    14

    Diiron Complexes with a Bridging Functionalized Allylidene Ligand: Synthesis, Structural Aspects, and Cytotoxicity

    Schoch, Silvia; Batchelor, Lucinda K.; Funaioli, Tiziana; Ciancaleoni, Gianluca; Zacchini, Stefano; Braccini, Simona; Chiellini, Federica; Biver, Tarita; Pampaloni, Guido; Dyson, Paul J.; Marchetti, Fabio

    Organometallics (2020), 39 (2), 361-373CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)

    Regio- and stereoselective nucleophilic attack of cyanide (from NBu4CN) to cationic diiron vinyliminium compds. [Fe2Cp2(CO)(μ-CO){μ-η1:η3-C(R')C(R'')CNMe2}]CF3SO3 ([1a-f]CF3SO3) affords the nitrile-aminoallylidene derivs. 2a-f in good to excellent yield. The analogous reaction of [1g]CF3SO3, comprising two different N substituents, gives 4 (63%) as a mixt. of two stereoisomers. [1G]CF3SO3, 2a-f, and 4 were characterized by IR and NMR spectroscopy and in a no. of cases by IR-spectroelectrochem. and single-crystal x-ray diffraction. The allylidene complexes are air-stable and robust in aq. soln.; however, in general they undergo oxidn. within a biol. relevant range of potentials. DFT calcns. were carried out to rationalize the obsd. stereoselectivity of the synthesis reaction and other structural and thermodn. aspects. The cytotoxicity of 2a-f was assessed on cisplatin-sensitive and -resistant human ovarian carcinoma (A2780 and A2780cisR) cell lines and human embryonic kidney (HEK-293) cells. Expts. reveal that treatment with the compds. leads to ROS prodn., with an absence of direct interactions with double-stranded DNA (calf thymus) and bovine serum albumin.
15. 15

    (a) Štarha, P.; Trávníček, Z. Non-platinum complexes containing releasable biologically active ligands. Coord. Chem. Rev. 2019, 395, 130– 145,  DOI: 10.1016/j.ccr.2019.06.001

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    Non-platinum complexes containing releasable biologically active ligands

    Starha, Pavel; Travnicek, Zdenek

    Coordination Chemistry Reviews (2019), 395 (), 130-145CODEN: CCHRAM; ISSN:0010-8545. (Elsevier B.V.)

    A review. Since the discovery of anticancer activity of cisplatin and other transition metal complexes, a lot of compds. have been reported as contg. ligand(s) bearing its(their) own biol. activity. Nowadays, the complexes contg. releasable bioactive ligand(s), for which several terms (e.g., multi-targeted, multi-action or multi-modal) have been introduced, represent one of the hottest topics for the bioinorg. chemists. Herein we focused on rationally designed cytotoxic complexes of platinum-group metals, namely ruthenium, rhodium, palladium, osmium and iridium, which contain releasable bioactive ligand(s). Because a concept of multi-targeted complexes is based on a release and subsequent joint biol. effect of multiple species, we conc. esp. on complexes whose fate under the (pseudo)physiol. conditions is provably or most likely connected with a release of bioactive ligand(s)/substituent(s) and cytotoxic metal-contg. species. Thus, the simultaneous action of the released species ensures various biol. profits, such as higher cytotoxic activity, cytotoxicity at different cells (connected with the ability to overcome resistance) or modified processes connected with the mode of action, as compared with the initial complexes without bioactive ligand(s).

    (b) Kilpin, K. J.; Dyson, P. J. Enzyme inhibition by metal complexes: concepts, strategies and applications. Chem. Sci. 2013, 4, 1410– 1419,  DOI: 10.1039/c3sc22349c

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    15b

    Enzyme inhibition by metal complexes: concepts, strategies and applications

    Kilpin, Kelly J.; Dyson, Paul J.

    Chemical Science (2013), 4 (4), 1410-1419CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)

    A review. Metal complexes are increasingly being used to inhibit enzymes. The reasons for this increased interest arise from the special features that metal complexes offer, e.g. the facile construction of 3D architectures that tightly fill enzyme active sites increasing selectivity and the possibility of facile coordination to protein residues that enhances enzyme inhibition. In this review we classify the main modes of enzyme inhibition by metal-based complexes and correlate the enzyme inhibition activity to macroscopic properties such as anticancer activity.
16. 16

    (a) Hanif, M.; Hartinger, C. G. From the hypothesis-driven development of organometallic anticancer drugs to new methods in mode of action studies. Adv. Inorg. Chem. 2020, 75, 339– 359,  DOI: 10.1016/bs.adioch.2019.10.007

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    16a

    From the hypothesis-driven development of organometallic anticancer drugs to new methods in mode of action studies

    Hanif, Muhammad; Hartinger, Christian G.

    Advances in Inorganic Chemistry (2020), 75 (Medicinal Chemistry), 339-359CODEN: AICHEP; ISSN:0898-8838. (Elsevier Ltd.)

    More often than rot, cancer patients are treated with chemotherapeutic cocktails that contain Pt-based drugs. Current research in the field of anticancer organometallics focuses on compds. with modes of action usually different from these drugs. Our research aims to design novel anticancer agents often based on bioactive ligands coordinated to metal centers, which results in synergistic effeas and properties neither of the components on their own would have. In this chapter, we summarize the development of selected compd. classes studied and describe how we employ a systematic approach when it comes to compd. design and informed decision making in anticancer metallodrug research.

    (b) Steel, T. R.; Walsh, F.; Wieczorek-Błauz, A.; Hanif, M.; Hartinger, C. G. Monodentately-coordinated bioactive moieties in multimodal half-sandwich organoruthenium anticancer agents. Coord. Chem. Rev. 2021, 439, 213890,  DOI: 10.1016/j.ccr.2021.213890

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    16b

    Monodentately-coordinated bioactive moieties in multimodal half-sandwich organoruthenium anticancer agents

    Steel, Tasha R.; Walsh, Fearghal; Wieczorek-Blauz, Anna; Hanif, Muhammad; Hartinger, Christian G.

    Coordination Chemistry Reviews (2021), 439 (), 213890CODEN: CCHRAM; ISSN:0010-8545. (Elsevier B.V.)

    A review. Metallodrugs have a central role in the treatment and diagnosis of diseases. To overcome potential toxicity and equip metal-based anticancer agents with biol. activity, the choice of the ligands coordinated to the metal center is essential. A recent strategy to address the shortcomings of current drugs and improve their targeted properties, is to introduce bioactive ligands, which may result in synergistic activity between the metal center and the ligand system. In this review, we discuss such efforts in the development of Ru half-sandwich compds., a class of promising anticancer agents which have been widely studied. We explore here strategies to introduce monodentately-coordinated bioactive moieties into such metal complexes by a variety of design concepts and review their potential as multimodal anticancer agents.

    (c) Gibson, D. Platinum(IV) anticancer agents; are we en route to the holy grail or to a dead end?. J. Inorg. Biochem. 2021, 217, 111353,  DOI: 10.1016/j.jinorgbio.2020.111353

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    16c

    Platinum(IV) anticancer agents; are we en route to the holy grail or to a dead end?

    Gibson, Dan

    Journal of Inorganic Biochemistry (2021), 217 (), 111353CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier Inc.)

    Pt(IV) complexes are designed as prodrugs that are intended to overcome resistance. Pt(IV) prodrugs are activated inside cancer cells releasing cytotoxic Pt(II) drugs as well as two axial ligands that can be used to confer favorable pharmacol. properties to the prodrug. The ligands can be innocent spectators, cancer targeting agents or bioactive moieties. The choice of axial ligands dets. the chem. and pharmacol. properties of the prodrugs. Over the years, several approaches were employed in attempts to increase the selectivity of the prodrugs to cancer cells and to utilize multi-action prodrugs to overcome resistance. In this review, we critically examine several of these approaches in order to evaluate the validity of some of the working hypotheses that are driving the current research.
17. 17

    (a) Studer, V.; Anghel, N.; Desiatkina, O.; Felder, T.; Boubaker, G.; Amdouni, Y.; Ramseier, J.; Hungerbühler, M.; Kempf, C.; Heverhagen, J. T.; Hemphill, A.; Ruprecht, N.; Furrer, J.; Pǎunescu, E. Conjugates Containing Two and Three Trithiolato-Bridged Dinuclear Ruthenium(II)-Arene Units as In Vitro Antiparasitic and Anticancer Agents. Pharmaceuticals 2020, 13, 471,  DOI: 10.3390/ph13120471

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    17a

    Conjugates containing two and three trithiolato-bridged dinuclear ruthenium(II)-arene units as in vitro antiparasitic and anticancer agents

    Studer, Valentin; Anghel, Nicoleta; Desiatkina, Oksana; Felder, Timo; Boubaker, Ghalia; Amdouni, Yosra; Ramseier, Jessica; Hungerbuehler, Martin; Kempf, Christoph; Heverhagen, Johannes Thomas; Hemphill, Andrew; Ruprecht, Nico; Furrer, Julien; Aunescu, Emilia P.

    Pharmaceuticals (2020), 13 (12), 471CODEN: PHARH2; ISSN:1424-8247. (MDPI AG)

    The synthesis, characterization, and in vitro antiparasitic and anticancer activity evaluation of new conjugates contg. two and three dinuclear trithiolato-bridged ruthenium(II)-arene units are presented. Antiparasitic activity was evaluated using transgenic Toxoplasma gondii tachyzoites constitutively expressing β-galactosidase grown in human foreskin fibroblasts (HFF). The compds. inhibited T. gondii proliferation with IC50 values ranging from 90 to 539 nM, and seven derivs. displayed IC50 values lower than the ref. compd. pyrimethamine, which is currently used for treatment of toxoplasmosis. Overall, compd. flexibility and size impacted on the anti-Toxoplasma activity. The anticancer activity of 14 compds. was assessed against cancer cell lines A2780, A2780cisR (human ovarian cisplatin sensitive and resistant), A24, (D-)A24cisPt8.0 (human lung adenocarcinoma cells wild type and cisPt resistant subline). The compds. displayed IC50 values ranging from 23 to 650 nM. In A2780cisR, A24 and (D-)A24cisPt8.0 cells, all compds. were considerably more cytotoxic than cisplatin, with IC50 values lower by two orders of magnitude. Irresp. of the nature of the connectors (alkyl/aryl) or the nos. of the di-ruthenium units (two/three), ester conjugates 6-10 and 20 exhibited similar antiproliferative profiles, and were more cytotoxic than amide analogs 11-14, 23, and 24. Polynuclear conjugates with multiple trithiolato-bridged di-ruthenium(II)-arene moieties deserve further investigation.

    (b) Reithofer, M. R.; Valiahdi, S. M.; Jakupec, M. A.; Arion, V. B.; Egger, A.; Galanski, M.; Keppler, B. K. Novel Di- and Tetracarboxylatoplatinum(IV) Complexes. Synthesis, Characterization, Cytotoxic Activity, and DNA Platination. J. Med. Chem. 2007, 50, 6692– 6699,  DOI: 10.1021/jm070897b

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    17b

    Novel Di- and Tetracarboxylatoplatinum(IV) Complexes. Synthesis, Characterization, Cytotoxic Activity, and DNA Platination

    Reithofer, Michael R.; Valiahdi, Seied M.; Jakupec, Michael A.; Arion, Vladimir B.; Egger, Alexander; Galanski, Markus; Keppler, Bernhard K.

    Journal of Medicinal Chemistry (2007), 50 (26), 6692-6699CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    Octahedrally configured diaminedichloro- and diamineoxalatoplatinum(IV) complexes with axial hydroxo ligands were carboxylated with succinic or glutaric anhydride. The free, uncoordinated carboxylic acid groups were further derivatized with amines and alcs. to the resp. amides and esters and characterized in detail by elemental anal., mass spectrometry, and multinuclear (1H, 13C, 15N, and 195Pt) NMR spectroscopy. Cytotoxicity of the complexes was studied in four human cancer cell lines derived from ovarian carcinoma (CH1, SK-OV-3), cervical carcinoma (HeLa), and colon carcinoma (SW480) by the MTT assay. Structure-activity relations revealed a low activity for Pt complexes with underivatized carboxylic acid moieties and amide derivs. displaying the hydroxyethylamino residue. Within amides, cyclopentylamino analogs were equipped with the highest cytotoxic potential. However, ester derivs. yielded IC50 values mostly in the low micromolar range and comparable to those of cisplatin. DNA platination studies of selected complexes revealed a high DNA platination capacity in parallel to a high cytotoxic potential and vice versa.

    (c) Cabrera, S.; Navas, F.; Matesanz, A. I.; Maroto, M.; Riedel, T.; Dyson, P. J.; Quiroga, A. G. Versatile Route to trans-Platinum(II) Complexes via Manipulation of a Coordinated 3-(Pyridin-3-yl)propanoic Acid Ligand. Inorg. Chem. 2019, 58, 7200– 7208,  DOI: 10.1021/acs.inorgchem.9b00126

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    17c

    Versatile Route to trans-Platinum(II) Complexes via Manipulation of a Coordinated 3-(Pyridin-3-yl)propanoic Acid Ligand

    Cabrera, Silvia; Navas, Francisco; Matesanz, Ana I.; Maroto, Marta; Riedel, Tina; Dyson, Paul J.; Quiroga, Adoracion G.

    Inorganic Chemistry (2019), 58 (11), 7200-7208CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)

    Authors describe the direct coupling of alcs. and amines to a 3-(pyridin-3-yl)propanoic acid ligand coordinated to a Pt(II) to afford ester and amide derivs. Using this approach, a family of trans-Pt(II) compds. with amine ligands bearing long perfluorinated chains was prepd., as these chains potentially endow the complexes with thermoactivatable properties. Related compds. with alkyl chains in place of the perfluorinated chains were also prepd. as controls using the same direct coupling method. The stability of the complexes in soln., their reactivity with DNA and proteins, and their antiproliferative activity evaluated in tumorigenic (A2780 and A2780cisR) and nontumorigenic (HEK293) cells at 37 °C and following exposure to elevated temps. (that mimic the temps. employed in thermotherapy) were also studied to assess their utility as putative (thermoactivated) anticancer agents.
18. 18

    Chellan, P.; Sadler, P. J. Enhancing the Activity of Drugs by Conjugation to Organometallic Fragments. Chem. - Eur. J. 2020, 26, 8676– 8688,  DOI: 10.1002/chem.201904699

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    18

    Enhancing the Activity of Drugs by Conjugation to Organometallic Fragments

    Chellan, Prinessa; Sadler, Peter J.

    Chemistry - A European Journal (2020), 26 (40), 8676-8688CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)

    A review. Resistance to chemotherapy is a current clin. problem, esp. in the treatment of microbial infections and cancer. One strategy to overcome this is to make new derivs. of existing drugs by conjugation to organometallic fragments, either by an appropriate linker, or by direct coordination of the drug to a metal. We illustrate this with examples of conjugated organometallic metallocene sandwich and half-sandwich complexes, RuII and OsII arene, and RhIII and IrIII cyclopentadienyl half-sandwich complexes. Ferrocene conjugates are particularly promising. The ferrocene-chloroquine conjugate ferroquine is in clin. trials for malaria treatment, and a ferrocene-tamoxifen deriv. (a ferrocifen) seems likely to enter anticancer trails soon. Several other examples illustrate that organometallic conjugation can restore the activity of drugs to which resistance has developed.
19. 19

    (a) Singh, A.; Lumb, I.; Mehra, V.; Kumar, V. Ferrocene-appended pharmacophores: an exciting approach for modulating the biological potential of organic scaffolds. Dalton Trans. 2019, 48, 2840– 2860,  DOI: 10.1039/C8DT03440K

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    19a

    Ferrocene-appended pharmacophores: an exciting approach for modulating the biological potential of organic scaffolds

    Singh, Amandeep; Lumb, Isha; Mehra, Vishu; Kumar, Vipan

    Dalton Transactions (2019), 48 (9), 2840-2860CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)

    A review. Two exemplary contributions of organometallics in medicinal chem., ferroquine and ferrocifen, which exhibit excellent anti-plasmodial and anti-cancer activities, resp., have opened a new field called medicinal organometallic chem. This field has been gaining significant interest due to the recent upsurge in ferrocene-linked org. frameworks with promising biol. potential. The success of ferrocene is due to the sustained efforts by org. medicinal chemists and its inherent stability in air, heat and light, low toxicity, low cost and reversible redox properties. The replacement of the aryl/heteroaryl core with a ferrocene nucleus in org. mols. imparts a significant change not only in their mol. properties, such as soly. and hydro-/lipophilicity, but also improves the activities of bioactive compds. Ferrocifen (ferrocene analog of hydroxytamoxifen) possesses the remarkable feature of being anti-proliferative against both the MCF-7 (hormone dependent) and MDA-MB-231 (hormone independent) breast cancer cell lines. Accordingly, this review article is aimed at updating researchers on the recent developments (2014-18) on the synthesis and evaluation of ferrocene-contg. bio-active pharmacophores with emphasis on their structure-activity relationship and mechanism of action.

    (b) Sansook, S.; Hassell-Hart, S.; Ocasio, C.; Spencer, J. Ferrocenes in medicinal chemistry; a personal perspective. J. Organomet. Chem. 2020, 905, 121017,  DOI: 10.1016/j.jorganchem.2019.121017

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    19b

    Ferrocenes in medicinal chemistry; a personal perspective

    Sansook, Supojjanee; Hassell-Hart, Storm; Ocasio, Cory; Spencer, John

    Journal of Organometallic Chemistry (2020), 905 (), 121017CODEN: JORCAI; ISSN:0022-328X. (Elsevier B.V.)

    A review. The authors present a short review of some of the recent work mainly targeting cancer-related oncoproteins through the development of primarily novel air- and water-stable iron-based organometallic agents. This work was presented at the recent ISBOMC19 conference at York as an invited lecture.

    (c) Wang, R.; Chen, H.; Yan, W.; Zheng, M.; Zhang, T.; Zhang, Y. Ferrocene-containing hybrids as potential anticancer agents: Current developments, mechanisms of action and structure-activity relationships. Eur. J. Med. Chem. 2020, 190, 112109,  DOI: 10.1016/j.ejmech.2020.112109

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    19c

    Ferrocene-containing hybrids as potential anticancer agents: Current developments, mechanisms of action and structure-activity relationships

    Wang, Ruo; Chen, Huahong; Yan, Weitao; Zheng, Mingwen; Zhang, Tesen; Zhang, Yaohuan

    European Journal of Medicinal Chemistry (2020), 190 (), 112109CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)

    A review. Cancer is one of the most fatal threatens to human health throughout the world. The major challenges in the control and eradication of cancers are the continuous emergency of drug-resistant cancer and the low specificity of anticancer agents, creating an urgent need to develop novel anticancer agents. Organometallic compds. esp. ferrocene derivs. possess remarkable structural and mechanistic diversity, inherent stability towards air, heat and light, low toxicity, low cost, reversible redox, ligand exchange, and catalytic properties, making them promising drug candidates for cancer therapy. Ferrocifen, a ferrocene-phenol hybrid, has demonstrated promising anticancer properties on drug-resistant cancers. Currently, Ferrocifen is in pre-clin. trial against cancers. Obviously, ferrocene moiety is a useful template for the development of novel anticancer agents. This review will provide an overview of ferrocene-contg. hybrids with potential application in the treatment of cancers covering articles published between 2010 and 2020. The mechanisms of action, the crit. aspects of design and structure-activity relationships are also discussed.

    (d) Błauz, A.; Rychlik, B.; Makal, A.; Szulc, K.; Strzelczyk, P.; Bujacz, G.; Zakrzewski, J.; Woẑniak, K.; Plaẑuk, D. Ferrocene–Biotin Conjugates: Synthesis, Structure, Cytotoxic Activity and Interaction with Avidin. ChemPlusChem 2016, 81, 1191– 1201,  DOI: 10.1002/cplu.201600320

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    19d

    Ferrocenyl-Biotin Conjugates: Synthesis, Structure, Cytotoxic Activity and Interaction with Avidin

    Blauz, Andrzej; Rychlik, Blazej; Makal, Anna; Szulc, Katarzyna; Strzelczyk, Pawel; Bujacz, Grzegorz; Zakrzewski, Janusz; Wozniak, Krzysztof; Plazuk, Damian

    ChemPlusChem (2016), 81 (11), 1191-1201CODEN: CHEMM5; ISSN:2192-6506. (Wiley-VCH Verlag GmbH & Co. KGaA)

    Friedel-Crafts acylation of ferrocene with D-biotin, D-homobiotin and D-desthiobiotin led to ferrocenyl ketones. These compds. were diastereoselectivly reduced to the corresponding alcs. using (R)- and (S)-Me-CBS-oxazaborolidine-borane complexes as reducing agents. The alcs. were further transformed to azido- and finally to amino-derivs. with retention of configuration, as confirmed by x-ray crystallog. Ferrocenyl biotin alcs. smoothly underwent dehydration to (E)-alkenes as a major isomers by heating in dild. HOAc. The synthesized compds. retained high affinity for avidin. They also exhibited high cytotoxic activities toward cancer cell lines with various levels of Na-Dependent Multivitamin Transporter (SMVT) in the absence of biotin in the medium, while the presence of free biotin in the medium decreased their antiproliferative activity. These biotin-ferrocene conjugates may be used as biol. active agents against cancer cells, although there was no clear relation between their cytotoxicity and cellular SMVT level.

    (e) Gimeno, M. C.; Goitia, H.; Laguna, A.; Luque, M. E.; Villacampa, M. D.; Sepúlveda, C.; Meireles, M. Conjugates of ferrocene with biological compounds. Coordination to gold complexes and antitumoral properties. J. Inorg. Biochem. 2011, 105, 1373– 1382,  DOI: 10.1016/j.jinorgbio.2011.07.015

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    19e

    Conjugates of ferrocene with biological compounds. Coordination to gold complexes and antitumoral properties

    Gimeno, M. Concepcion; Goitia, Helen; Laguna, Antonio; Luque, M. Elvira; Villacampa, M. Dolores; Sepulveda, Catarina; Meireles, Margarida

    Journal of Inorganic Biochemistry (2011), 105 (11), 1373-1382CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier)

    Six bioconjugates of ferrocene with biol. compds. such as amino acid esters and related species were prepd. by reaction of chlorocarbonyl ferrocene with the corresponding amino acid ester (histidine Me ester, tryptophan Me ester, methionine Me ester and lysine Et ester) or histamine or prolinamide in the presence of NEt3. The reaction of the tryptophan or prolinamide ferrocene conjugates with [Au(acac)(PR3)] (acac = acetylacetonate, R = Ph, pyridine, C6F5) results in the substitution of the proton of the cyclic NH groups by the fragment AuPR3+ affording [Au(FcCO-tryptophan-OMe)(PR3)] or [Au(FcCO-prolinamide)(PR3)] (Fc = ferrocenyl group). The reaction of FcCO-Met-OMe with [Au(OTf)(PR3)] (OTf = trifluoromethylsulfonate) or [Au(C6F5)3(OEt2)] yields the Au(I) or Au(III) derivs. [Au(FcCO-Met-OMe)(PR3)]OTf or [Au(C6F5)3(FcCO-Met-OMe)], resp. Cytotoxicity studies towards several cancer lines such as MCF-7, HeLa or NIE-115 were performed. The ferrocene bioconjugates show no activity whereas the Au complexes exhibit antiproliferative effect. Preliminary studies of interaction of compds. with cells were carried out with the goal of increasing the authors' knowledge on the mechanism of action of these potential drugs.
20. 20

    Prinz, C.; Vasyutina, E.; Lohmann, G.; Schrader, A.; Romanski, S.; Hirschhäuser, C.; Mayer, P.; Frias, C.; Herling, C. D.; Hallek, M.; Schmalz, H.-G.; Prokop, A.; Mougiakakos, D.; Herling, M. Organometallic nucleosides induce non-classical leukemic cell death that is mitochondrial-ROS dependent and facilitated by TCL1-oncogene burden. Mol. Cancer 2015, 14, 114,  DOI: 10.1186/s12943-015-0378-1

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    20

    Organometallic nucleosides induce non-classical leukemic cell death that is mitochondrial-ROS dependent and facilitated by TCL1-oncogene burden

    Prinz Christian; Vasyutina Elena; Lohmann Gregor; Schrader Alexandra; Mayer Petra; Herling Marco; Romanski Steffen; Hirschhauser Christoph; Schmalz Hans-Gunther; Frias Corazon; Prokop Aram; Herling Carmen D; Hallek Michael; Mougiakakos Dimitrios

    Molecular cancer (2015), 14 (), 114 ISSN:.

    BACKGROUND: Redox stress is a hallmark of the rewired metabolic phenotype of cancer. The underlying dysregulation of reactive oxygen species (ROS) is interconnected with abnormal mitochondrial biogenesis and function. In chronic lymphocytic leukemia (CLL), elevated ROS are implicated in clonal outgrowth and drug resistance. The pro-survival oncogene T-cell leukemia 1 (TCL1) is causally linked to the high threshold towards classical apoptosis in CLL. We investigated how aberrant redox characteristics and bioenergetics of CLL are impacted by TCL1 and if this is therapeutically exploitable. METHODS: Bio-organometallic chemistry provided compounds containing a cytosine nucleobase, a metal core (ferrocene, ruthenocene, Fe(CO)3), and a 5'-CH2O-TDS substituent. Four of these metal-containing nucleoside analogues (MCNA) were tested for their efficacy and mode of action in CLL patient samples, gene-targeted cell lines, and murine TCL1-transgenic splenocytes. RESULTS: The MCNA showed a marked and selective cytotoxicity towards CLL cells. MCNA activity was equally observed in high-risk disease groups, including those of del11q/del17p cytogenetics and of clinical fludarabine resistance. They overcame protective stromal cell interactions. MCNA-evoked PARP-mediated cell death was non-autophagic and non-necrotic as well as caspase- and P53-independent. This unconventional apoptosis involved early increases of ROS, which proved indispensible based on mitigation of MCNA-triggered death by various scavengers. MCNA exposure reduced mitochondrial respiration (oxygen consumption rate; OCR) and induced a rapid membrane depolarization (αΨM). These characteristics distinguished the MCNA from the alkylator bendamustine and from fludarabine. Higher cellular ROS and increased MCNA sensitivity were linked to TCL1 expression. The presence of TCL1 promoted a mitochondrial release of in part caspase-independent apoptotic factors (AIF, Smac, Cytochrome-c) in response to MCNA. Although basal mitochondrial respiration (OCR) and maximal respiratory capacity were not affected by TCL1 overexpression, it mediated a reduced aerobic glycolysis (lactate production) and a higher fraction of oxygen consumption coupled to ATP-synthesis. CONCLUSIONS: Redox-active substances such as organometallic nucleosides can confer specific cytotoxicity to ROS-stressed cancer cells. Their P53- and caspase-independent induction of non-classical apoptosis implicates that redox-based strategies can overcome resistance to conventional apoptotic triggers. The high TCL1-oncogenic burden of aggressive CLL cells instructs their particular dependence on mitochondrial energetic flux and renders them more susceptible towards agents interfering in mitochondrial homeostasis.
21. 21

    Aspirin:Cheng, Q.; Shi, H.; Wang, H.; Min, Y.; Wang, J.; Liu, Y. The ligation of aspirin to cisplatin demonstrates significant synergistic effects on tumor cells. Chem. Commun. 2014, 50, 7427– 7430,  DOI: 10.1039/C4CC00419A

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    21

    The ligation of aspirin to cisplatin demonstrates significant synergistic effects on tumor cells

    Cheng, Qinqin; Shi, Hongdong; Wang, Hongxia; Min, Yuanzeng; Wang, Jun; Liu, Yangzhong

    Chemical Communications (Cambridge, United Kingdom) (2014), 50 (56), 7427-7430CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)

    Asplatin, a fusion of aspirin and cisplatin, exhibits significant cytotoxicity in tumor cells and almost fully overcomes the drug resistance of cisplatin resistant cells. Asplatin is highly accumulated in cancer cells and is activated upon the redn. by ascorbic acid.
22. 22

    Chlorambucil:

    (a) Qin, X.; Fang, L.; Chen, F.; Gou, S. Conjugation of platinum(IV) complexes with chlorambucil to overcome cisplatin resistance via a “joint action” mode toward DNA. Eur. J. Med. Chem. 2017, 137, 167– 175,  DOI: 10.1016/j.ejmech.2017.05.056

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    22a

    Conjugation of platinum(IV) complexes with chlorambucil to overcome cisplatin resistance via a "joint action" mode toward DNA

    Qin, Xiaodong; Fang, Lei; Chen, Feihong; Gou, Shaohua

    European Journal of Medicinal Chemistry (2017), 137 (), 167-175CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)

    Two platinum(IV) complexes were designed and prepd. by conjugation of cisplatin and oxaliplatin units with a DNA-damaging agent, chlorambucil, resp. By taking a joint action to enhance the damage of DNA, the conjugates displayed potent antitumor activity against all the tested cancer cell lines comparable to cisplatin and oxaliplatin, and notably could overcome cisplatin resistance at certain degree. Complex [Pt(NH3)2Cl2(OCO(CH2)3-p-C6H4-N(CH2CH2Cl)2)] (I), a hybrid of cisplatin and chlorambucil, arrested the cell cycle at the S and G2 phases, distinctive from those of cisplatin and oxaliplatin. Apoptosis studies revealed that complex 4 could induce cell apoptosis significantly in both SGC7901 and SGC7901/CDDP cells. Moreover, further investigation indicated that complex I suppressed the drug resistance by the improvement of the platinum uptake and the inhibition of PARP-1 protein. These results show that the "joint action" on DNA is an effective strategy to overcome cisplatin resistance.

    (b) Nazarov, A. A.; Meier, S. M.; Zava, O.; Nosova, Y. N.; Milaeva, E. R.; Hartinger, C. G.; Dyson, P. J. Protein ruthenation and DNA alkylation: chlorambucil-functionalized RAPTA complexes and their anticancer activity. Dalton Trans. 2015, 44, 3614– 3623,  DOI: 10.1039/C4DT02764G

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    22b

    Protein ruthenation and DNA alkylation: chlorambucil-functionalized RAPTA complexes and their anticancer activity

    Nazarov, Alexey A.; Meier, Samuel M.; Zava, Olivier; Nosova, Yulia N.; Milaeva, Elena R.; Hartinger, Christian G.; Dyson, Paul J.

    Dalton Transactions (2015), 44 (8), 3614-3623CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)

    Chemotherapeutics for the treatment of tumorigenic conditions that feature novel modes of action are highly sought after to overcome the limitations of current chemotherapies. Herein, we report the conjugation of the alkylating agent chlorambucil to the RAPTA scaffold, a well-established pharmacophore. While chlorambucil is known to alkylate DNA, the RAPTA complexes are known to coordinate to amino acid side chains of proteins. Therefore, such a mol. combines DNA and protein targeting properties in a single mol. Several chlorambucil-tethered RAPTA derivs. were prepd. and tested for their cytotoxicity, stability in water and reactivity to protein and DNA substrates. The anticancer activity of the complexes is widely driven by the cytotoxicity of the chlorambucil moiety. However, esp. in the cisplatin-resistant A2780R cells, the chlorambucil-functionalized RAPTA derivs. are in general more cytotoxic than chlorambucil and also a mixt. of chlorambucil and the parent organoruthenium RAPTA compd. In a proof-of-principle expt., the crosslinking of DNA and protein fragments by a chlorambucil-RAPTA deriv. was obsd.
23. 23

    Fiala, C.; Pasic, M. D. Aspirin: Bitter pill or miracle drug?. Clin. Biochem. 2020, 85, 1– 4,  DOI: 10.1016/j.clinbiochem.2020.07.003

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    23

    Aspirin: Bitter pill or miracle drug?

    Fiala, Clare; Pasic, Maria D.

    Clinical Biochemistry (2020), 85 (), 1-4CODEN: CLBIAS; ISSN:0009-9120. (Elsevier B.V.)

    A review. Acetylsalicylic acid (ASA) or brand name Aspirin is a widely available medication used to relieve inflammation, fever and pain. It has also been frequently prescribed as prevention for cardiovascular disease due to its anti-thrombotic qualities. However, ASA is also connected to increased internal bleeding, leading to concerns that this harmful side effect may outweigh its cardioprotective properties in some populations. In this review, we summarize data from several recent, large-scale clin. trials that put into the question the long-standing recommendations about prescribing ASA for primary cardiovascular disease. We also provide a detailed overview of the role of ASA in cancer, surgery and female reproductive health. Finally, we discuss the ASA prescription guidelines of several major medical organizations and suggest that this new evidence may lead to updates to these influential and longstanding recommendations.
24. 24

    Goede, V.; Eichhorst, B.; Fischer, K.; Wendtner, C.-M.; Hallek, M. Past, present and future role of chlorambucil in the treatment of chronic lymphocytic leukemia. Leuk. Lymphoma 2015, 56, 1585– 1592,  DOI: 10.3109/10428194.2014.963077

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    24

    Past, present and future role of chlorambucil in the treatment of chronic lymphocytic leukemia

    Goede, Valentin; Eichhorst, Barbara; Fischer, Kirsten; Wendtner, Clemens-Martin; Hallek, Michael

    Leukemia & Lymphoma (2015), 56 (6), 1585-1592CODEN: LELYEA; ISSN:1029-2403. (Informa Healthcare)

    For many decades, chlorambucil was the std. of care for chronic lymphocytic leukemia (CLL), but meanwhile has been replaced by purine analog-based chemoimmunotherapy. Monotherapy with the alkylator only retained significance in the treatment of older patients unfit for std. treatment. After successful phase II studies, recent phase III trials established combinations of chlorambucil with anti-CD20 antibodies such as rituximab, ofatumumab and obinutuzumab as a valuable treatment option for these patients. Today, chlorambucil therefore should be used as a chemotherapy backbone for antibody-based chemoimmunotherapy in this patient population rather than as monotherapy. Starting from the past role of chlorambucil in CLL treatment, we here review the most recent efforts to elaborate chlorambucil-based chemoimmunotherapy in CLL and discuss clin. relevant questions that arise from this approach.
25. 25

    Rubner, G.; Bensdorf, K.; Wellner, A.; Kircher, B.; Bergemann, S.; Ott, I.; Gust, R. Synthesis and Biological Activities of Transition Metal Complexes Based on Acetylsalicylic Acid as Neo-Anticancer Agents. J. Med. Chem. 2010, 53, 6889– 6898,  DOI: 10.1021/jm101019j

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    25

    Synthesis and Biological Activities of Transition Metal Complexes Based on Acetylsalicylic Acid as Neo-Anticancer Agents

    Rubner, Gerhard; Bensdorf, Kerstin; Wellner, Anja; Kircher, Brigitte; Bergemann, Silke; Ott, Ingo; Gust, Ronald

    Journal of Medicinal Chemistry (2010), 53 (19), 6889-6898CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    [(μ4-η2)-(Prop-2-ynyl)-2-acetoxybenzoate]dicobalt hexacarbonyl (Co-ASS), a deriv. of aspirin (ASS), demonstrated high growth-inhibitory potential against various tumor cells with interference in the arachidonic acid cascade as probable mode of action. The significance of the kind of metal and cluster was verified in this structure-activity study: Co2(CO)6 was resp. exchanged by a tetrameric cobalt-, trimeric ruthenium-, or trimeric iron carbonyl cluster. Furthermore, the metal binding motif was changed from alkyne to 1,3-butadiene. Compds. were evaluated for growth inhibition, antiproliferative effects, and apoptosis induction in breast (MCF-7, MDA-MB 231) and colon cancer (HT-29) cell lines and for COX-1/2 inhibitory effects at isolated isoenzymes. Addnl., the major COX metabolite prostaglandin E2 (PGE2) was quantified in arachidonic acid-stimulated MDA-MB 231 breast tumor cells. It was demonstrated that the metal cluster was of minor importance for effects on cellular activity if an alkyne was used as ligand. Generally, no correlation existed between growth inhibition and COX activity. Cellular growth inhibition and antiproliferative activity at higher concns. of the most active compds. correlated well with apoptosis induction.
26. 26

    Biancalana, L.; Batchelor, L. K.; Funaioli, T.; Zacchini, S.; Bortoluzzi, M.; Pampaloni, G.; Dyson, P. J.; Marchetti, F. α-Diimines as Versatile, Derivatizable Ligands in Ruthenium(II) p-Cymene Anticancer Complexes. Inorg. Chem. 2018, 57, 6669– 6685,  DOI: 10.1021/acs.inorgchem.8b00882

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    26

    α-Diimines as Versatile, Derivatizable Ligands in Ruthenium(II) p-Cymene Anticancer Complexes

    Biancalana, Lorenzo; Batchelor, Lucinda K.; Funaioli, Tiziana; Zacchini, Stefano; Bortoluzzi, Marco; Pampaloni, Guido; Dyson, Paul J.; Marchetti, Fabio

    Inorganic Chemistry (2018), 57 (11), 6669-6685CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)

    Ruthenium half-sandwich η6-p-cymene cationic diimine complexes [(η6-cymene)RuCl(RN:CHCHNR)][NO3] (R = Cy, 4-HOC6H10, 4-HOC6H4, 2-MeCO2C6H4OCOC6H4, 4-C7H15OCOC6H4) were prepd. and examd. for cytotoxicity and antitumor activity. α-Diimines are among the most robust and versatile ligands available in synthetic coordination chem., possessing finely tunable steric and electronic properties. A series of novel cationic ruthenium(II) p-cymene complexes bearing simple α-diimine ligands, [(η6-p-cymene)RuCl{κ2N-(HCNR)2}]NO3 (1-3; R = Cy, 4-C6H10OH, 4-C6H4OH), were prepd. in near-quant. yields as their nitrate salts. [2]NO3 displays high water soly. The potential of the α-diimine ligand in [3]NO3 as a carrier of bioactive mols. was investigated via esterification reactions with the hydroxyl groups. Thus, the double-functionalized derivs. [(η6-p-cymene)RuCl{κ2N-(HCN(4-C6H4OCO-R))2}]NO3 (4, 5, 6; R = Me, 2-MeCO2C6H4, 4-C7H15) were obtained in good-to-high yields. UV-vis and multinuclear NMR spectroscopy and cyclic voltammetric studies in aq. soln. revealed only minor ruthenium chloride hydrolytic cleavage, biol. accessible redn. potentials, and pH-dependent behavior of [3]NO3. D. functional theory anal. was performed in order to compare the Ru-Cl bond strength in [1]+ with the analogous ethylenediamine complex, showing that the higher stability obsd. in the former is related to the electron-withdrawing properties of the α-diimine ligand. In vitro cytotoxicity studies were performed against tumorigenic (A2780 and A2780cisR) and nontumorigenic (HEK-293) cell lines, with the complexes bearing simple α-diimine ligands ranging from inactive to IC50 values in the low micromolar range. The complexes functionalized with bioactive components, i.e., [5]NO3 and [6]NO3, exhibited a marked increase in the cytotoxicity with respect to the precursor [3]NO3.
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    Liu, J.; Huang, W.; Pang, Y.; Zhu, X.; Zhou, Y.; Yan, D. Hyperbranched Polyphosphates for Drug Delivery Application: Design, Synthesis, and In Vitro Evaluation. Biomacromolecules 2010, 11, 1564– 1570,  DOI: 10.1021/bm100188h

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    Hyperbranched Polyphosphates for Drug Delivery Application: Design, Synthesis, and In Vitro Evaluation

    Liu, Jinyao; Huang, Wei; Pang, Yan; Zhu, Xinyuan; Zhou, Yongfeng; Yan, Deyue

    Biomacromolecules (2010), 11 (6), 1564-1570CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)

    A water-sol. hyperbranched polyphosphate (HPHEEP) was synthesized through the self-condensation ring-opening polymn. (SCROP) of 2-(2-hydroxyethoxy)ethoxy-2-oxo-1,3,2-dioxaphospholane (HEEP), and its suitability as a drug carrier was then evaluated in vitro. Me tetrazolium (MTT) and live/dead staining assays indicated that HPHEEP had excellent biocompatibility against COS-7 cells. The good biodegradability of HPHEEP was obsd. by NMR anal., and the degrdn. products were nontoxic to COS-7 cells. Flow cytometry and confocal laser scanning microscopy analyses suggested that HPHEEP could be easily internalized by vivid cells and preferentially accumulated in the perinuclear region. Furthermore, a hydrophobic anticancer drug, chlorambucil, was used as a model drug and covalently bound to HPHEEP. The chlorambucil dose of the conjugate and free drug required for 50% cellular growth inhibition were 75 and 50 μg/mL, resp., according to MTT assay against an MCF-7 breast cancer cell line in vitro. This high activity of the conjugate may be attributed to the biodegradability of HPHEEP so as to release the chlorambucil in cells. Therefore, on the basis of its biocompatibility and biodegradability, HPHEEP could provide a charming opportunity to design some excellent drug delivery systems for therapeutic applications.
28. 28

    Agonigi, G.; Bortoluzzi, M.; Marchetti, F.; Pampaloni, G.; Zacchini, S.; Zanotti, V. Regioselective Nucleophilic Additions to Diiron Carbonyl Complexes Containing a Bridging Aminocarbyne Ligand: A Synthetic, Crystallographic and DFT Study. Eur. J. Inorg. Chem. 2018, 2018, 960– 971,  DOI: 10.1002/ejic.201701115

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    Regioselective Nucleophilic Additions to Diiron Carbonyl Complexes Containing a Bridging Aminocarbyne Ligand: A Synthetic, Crystallographic and DFT Study

    Agonigi, Gabriele; Bortoluzzi, Marco; Marchetti, Fabio; Pampaloni, Guido; Zacchini, Stefano; Zanotti, Valerio

    European Journal of Inorganic Chemistry (2018), 2018 (8), 960-971CODEN: EJICFO; ISSN:1434-1948. (Wiley-VCH Verlag GmbH & Co. KGaA)

    Diiron μ-aminocarbyne compds., [Fe2{μ-CN(Me)(R)}(μ-CO)(CO)2(Cp)2][SO3CF3] (1: R = Me (a), Bn (b), Xyl (2,6-C6H3Me2, c), 2-Cl-6-MeC6H3 (d), naphthyl (e)), were prepd. in two steps from Fe2Cp2(CO)4, negating the need for difficult purifn. procedures of intermediate species; they are efficiently isolated by alumina chromatog. Minor amts. of μ-aminocarbyne aryl isocyanide compds., [Fe2{μ-CN(Me)(R)}(μ-CO)(CO)(CNR)(Cp)2][SO3CF3] (2: R = Xyl (a), 2-Cl-6-MeC6H3 (b), 2-naphthyl (c)), were obtained as side products. The structures of the cations in 1a,c,e are calcd. using DFT; the carbyne C is generally predicted to be the thermodn. site of hydride addn., in agreement with a previous exptl. finding concerning 1a. Accordingly, the reaction of 1e with NaBH4 affords a bridging aminocarbene complex, [Fe2{μ-CH(NMe(C10H7))}(μ-CO)(CO)2Cp2] (4), in 85% yield. Otherwise, the reaction of 1c with NaBH4 yields the aminocarbyne-cyclopentadiene deriv. [Fe2{μ-CNMe(Xyl)}(μ-CO)(CO)2Cp(η4-C5H6)] (3, 70 %), presumably as a consequence of the steric protection exerted by the xylyl-Me groups towards the carbyne moiety. The sequential treatment of 1a,c with Li2CuCNMe2 and MeSO3CF3 affords [Fe2{μ-CN(Me)(R)}(μ-CO)(CO){C(OMe)Me}Cp2][SO3CF3] (5: R = Me (a), Xyl (b)), comprising both aminocarbyne and alkoxycarbene ligands. In accordance with DFT calcns., the alkoxycarbene moiety in 5a is the most favorable site for nucleophilic attack. Thus, the reactions of 5a with NH2R (R = Et, iPr) and NBu4CN, resp., give the aminocarbyne/aminocarbene complexes, [Fe2(μ-CNMe2)(μ-CO)(CO){C(Me)NH(R)}(Cp)2][SO3CF3] (6: R = iPr (a), Et (b)), and the aminocarbyne-α-cyanoalkyl [Fe2(μ-CNMe2)(μ-CO)(CO){C(CN)(OMe)Me}Cp2] (7). All the products are fully characterized by spectroscopic and anal. methods; moreover, the structures of 1a, 1d, 6a and 7 are elucidated by single-crystal x-ray diffraction studies.
29. 29

    Albano, V. G.; Busetto, L.; Marchetti, F.; Monari, M.; Zacchini, S.; Zanotti, V. Stereochemistry of the insertion of disubstituted alkynes into the metal aminocarbyne bond in diiron complexes. J. Organomet. Chem. 2004, 689, 528– 538,  DOI: 10.1016/j.jorganchem.2003.11.003

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    Stereochemistry of the insertion of disubstituted alkynes into the metal aminocarbyne bond in diiron complexes

    Albano, Vincenzo G.; Busetto, Luigi; Marchetti, Fabio; Monari, Magda; Zacchini, Stefano; Zanotti, Valerio

    Journal of Organometallic Chemistry (2004), 689 (3), 528-538CODEN: JORCAI; ISSN:0022-328X. (Elsevier Science B.V.)

    Terminal alkynes HC≡CR'(R' = COOMe, CH2OH) insert into the metal-carbyne bond of diiron complexes [Fe2{μ-CN(Me)(R)}(μ-CO)(CO)(NCMe)(Cp)2][SO3CF3] (R = Xyl, 1a; CH2Ph, 1b; Me, 1c; Xyl = 2,6-Me2C6H3), affording the corresponding μ-vinyliminium complexes [Fe2{μ-σ:η3-C(R'):CHC:N(Me)(R)}(μ-CO)(CO)(Cp)2][SO3CF3] (R = Xyl, R' = COOMe, 2; R = CH2Ph, R' = COOMe, 3; R = Me, R' = COOMe, 4; R = Xyl, R' = CH2OH, 5; R = Me, R' = CH2OH, 6). The insertion is regiospecific and C-C bond formation selectively occurs between the carbyne carbon and the CH moiety of the alkyne. Disubstituted alkynes R'C≡CR' also insert into the metal-carbyne bond leading to the formation of [Fe2{μ-σ:η3-C(R'):C(R')C:N(Me)(R)}(μ-CO)(CO)(Cp)2][SO3CF3] (R' = Me, R = Xyl, 8; R' = Et, R = Xyl, 9; R' = COOMe, R = Xyl, 10; R' = COOMe, R = CH2Ph, 11; R' = COOMe, R = Me, 12). Complexes 2, 3, 5, 8, 9 and 11, in which the iminium nitrogen is unsym. substituted, give rise to E and/or Z isomers. When iminium substituents are Me and Xyl, the NMR and structural investigations (x-ray structure anal. of 2 and 8) indicate that complexes obtained from terminal alkynes preferentially adopt the E configuration, whereas those derived from internal alkynes are exclusively Z. In complexes 8 and 9, trans and cis isomers have been obsd., by NMR spectroscopy, and the structures of trans-8 and cis-8 have been detd. by x-ray diffraction studies. Trans to cis isomerization occurs upon heating in THF at reflux temp. In contrast to the case of HC≡CR', the insertion of 2-hexyne is not regiospecific: both [Fe2{μ-σ:η3-C(CH2CH2CH3):C(Me)C:N(Me)(R)}(μ-CO)(CO)(Cp)2][SO3CF3] (R = Xyl, 13; R = Me, 15) and [Fe2{μ-σ:η3-C(Me):C(CH2CH2CH3)C:N(Me)(R)}(μ-CO)(CO)(Cp)2][SO3CF3] (R = Xyl, 14, R = Me, 16) are obtained and these compds. are present in soln. as a mixt. of cis and trans isomers, with predominance of the former.
30. 30

    Biancalana, L.; Batchelor, L. K.; De Palo, A.; Zacchini, S.; Pampaloni, G.; Dyson, P. J.; Marchetti, F. A general strategy to add diversity to ruthenium arene complexes with bioactive organic compounds via a coordinated (4-hydroxyphenyl) diphenylphosphine ligand. Dalton Trans. 2017, 46, 12001– 12004,  DOI: 10.1039/C7DT02062G

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    A general strategy to add diversity to ruthenium arene complexes with bioactive organic compounds via a coordinated (4-hydroxyphenyl)diphenylphosphine ligand

    Biancalana, Lorenzo; Batchelor, Lucinda K.; De Palo, Alice; Zacchini, Stefano; Pampaloni, Guido; Dyson, Paul J.; Marchetti, Fabio

    Dalton Transactions (2017), 46 (36), 12001-12004CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)

    Esterification of (4-hydroxyphenyl)diphenylphosphine, coordinated to the [Ru(η6-p-cymene)Cl2] fragment, allows a series of bioactive carboxylic acids to be introduced directly into the organometallic mol. Evaluation of the compds. on human ovarian cancer cells reveals synergistic enhancements in their antiproliferative activity relative to their bioactive org. and organometallic precursors.
31. 31

    The previously reported value was aspirin 1160 mM:Makkar, F.; Chakraborty, K. First report of dual cyclooxygenase-2 and 5-lipoxygenase inhibitory halogen derivatives from the thallus of intertidal seaweed Kappaphycus alvarezii. Med. Chem. Res. 2018, 27, 2331– 2340,  DOI: 10.1007/s00044-018-2239-0

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    First report of dual cyclooxygenase-2 and 5-lipoxygenase inhibitory halogen derivatives from the thallus of intertidal seaweed Kappaphycus alvarezii

    Makkar, Fasina; Chakraborty, Kajal

    Medicinal Chemistry Research (2018), 27 (10), 2331-2340CODEN: MCREEB; ISSN:1054-2523. (Springer)

    Two halogen derivs., characterized as 2-butyl-7-4-(chloromethyl) (cyclooct-1-enyl) hept-5-en-1-ol (compd. 1) and 4-(2-chloroethyl)-5-7-(methoxymethyl) (undec-3-enyl) cyclooct-4-enone (compd. 2) were isolated from the Et acetate-methanol ext. of the intertidal red seaweed Kappaphycus alvarezii. The studied compds. were evaluated for their inhibitory effects towards pro-inflammatory 5-lipoxygenase along with cyclooxygenases, and also were detd. the free radical scavenging potential. The halogenated cyclooctenone (compd. 2) displayed greater 5-lipoxygenase (IC50 0.90 mg mL-1) inhibitory activity when compared to the non steroidal anti-inflammatory drug ibuprofen (IC50 0.93 mg mL-1). Similarly selectivity indexes of the studied compds. were higher (anti-cyclooxygense-1 IC50/anti-cyclooxygense-2 IC50 ∼1.06-1.07) when compared to those displayed by ibuprofen (0.44) and aspirin (0.02). The antioxidative activities of the halogen derivs. were found to be greater (IC50 < 0.30 mg mL-1) in comparison with that exhibited by α-tocopherol (IC50 > 0.50 mg mL-1). This is the first report on structural characterization of unusual halogen analogs from K. alvarezii with dual cyclooxygenase-2 and 5-lipoxygenase inhibitory activities.
32. 32

    Macii, F.; Biver, T. Spectrofluorimetric analysis of the binding of a target molecule to serum albumin: tricky aspects and tips. J. Inorg. Biochem. 2021, 216, 111305,  DOI: 10.1016/j.jinorgbio.2020.111305

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    Spectrofluorimetric analysis of the binding of a target molecule to serum albumin: tricky aspects and tips

    Macii, Francesca; Biver, Tarita

    Journal of Inorganic Biochemistry (2021), 216 (), 111305CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier Inc.)

    Protein binding heavily modulates drug activity. Therefore, the binding features need to be elucidated when chem. researchers study new mols. (metal complexes) to be used as drugs. This paper concerns the exptl. and data treatment aspects of the mechanistic anal. of the binding to a fluorescent protein (the golden std. serum albumin) by using direct fluorescence titrns. Fluorescence data are not rarely only qual. used, neglecting further treatments which could offer a precious detailed picture of the behavior of the drug. We aim to spread a mechanistic approach, discussing the crit. aspects for correctly designing the expts. and treating the data. The researcher may confirm adduct formation and evaluate binding consts. (Stern-Volmer KSV or other types of K). Also, we discuss here, with the help of literature examples, the correct use of temp. dependence of K to ext. thermodn. parameters, comment on enthalpy-entropy compensation, together with the use of synchronous spectra and exchange expts. to gain information on the binding type and site. We think that this tutorial/crit. synopsis can be of help for the increasing community dealing with these expts., which are valuable but often much more tricky than it might appear at first sight.
33. 33

    HypSpec2014 software; http://www.hyperquad.co.uk/.

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    There is no corresponding record for this reference.
34. 34

    (a) Tǒpala, T.; Pascual-Álvarez, A.; Moldes-Tolosa, M. Á.; Bodoki, A.; Castiñeiras, A.; Torres, J.; del Pozo, C.; Borrás, J.; Alzuet-Piña, G. New sulfonamide complexes with essential metal ions [Cu(II), Co(II), Ni(II) and Zn(II)]. Effect of the geometry and the metal ion on DNA binding and nuclease activity. BSA protein interaction. J. Inorg. Biochem. 2020, 202, 110823,  DOI: 10.1016/j.jinorgbio.2019.110823

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    34a

    New sulfonamide complexes with essential metal ions [Cu (II), Co (II), Ni (II) and Zn (II)]. Effect of the geometry and the metal ion on DNA binding and nuclease activity. BSA protein interaction

    Topala Tamara; Pascual-Alvarez Alejandro; Moldes-Tolosa M Angeles; Borras Joaquin; Bodoki Andreea; Castineiras Alfonso; Torres Javier; Del Pozo Carlos; Alzuet-Pina Gloria

    Journal of inorganic biochemistry (2020), 202 (), 110823 ISSN:.

    Mixed divalent Cu, Co, Ni and Zn complexes containing the new sulfonamide ligand N-(2-(pyridin-2-yl)ethyl)quinoline-8-sulfonamide (HQSEP) were prepared and characterized by physico-chemical techniques. The tetracoordinate [Cu(QSEP)X] [X = Br (1), Cl (2)] compounds present a seesaw geometry (τ4 = 0.56 (1) and 0.50 (2)). The Cu(II) in the [Cu(QSEP)(NO3)(MeOH)] (3) complex is five coordinate with a slightly distorted SP geometry (τ = 0.11). The [M(QSEP)(benz)] [M = Cu(II) (4), Ni(II) (5), Co(II) (6) and Zn(II) (7); benz = benzoate] compounds are configurationally isotypic. The coordination geometries of the M(II) ions can be best described as distorted SP (τ = 0.29, 0.15, 0.34 and 0.18 for 4, 5, 6 and 7, respectively). The interaction of the compounds with CT-DNA was studied by different techniques. Notably, these studies indicated that the tetracoordinate complexes (1 and 2) present higher DNA affinity than pentacoordinate compounds (3-7). In line with the Irving-Williams order of stability, 5 presented higher propensity for DNA binding than 6. Interestingly, the cleavage activity of 1-4 in the presence of ascorbate/H2O2 follows the same trend as that found for DNA binding affinity, being the tetracoordinate 1 and 2 more effective as nucleases than the five coordinate 3 and 4. Also, the DNA cleavage reaction mechanism was investigated. DNA cleavage experiments upon irradiation indicated the important role of the aromatic nature of the coligand in the photocleavage activity of 1-4. Finally, the interaction of the compounds with bovine serum albumin (BSA) was studied and the binding constants were calculated.

    (b) Elsadek, B.; Kratz, F. Impact of albumin on drug delivery-New applications on the horizon. J. Controlled Release 2012, 157, 4– 28,  DOI: 10.1016/j.jconrel.2011.09.069

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    34b

    Impact of albumin on drug delivery - New applications on the horizon

    Elsadek, Bakheet; Kratz, Felix

    Journal of Controlled Release (2012), 157 (1), 4-28CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)

    A review. Over the past decades, albumin has emerged as a versatile carrier for therapeutic and diagnostic agents, primarily for diagnosing and treating diabetes, cancer, rheumatoid arthritis and infectious diseases. Market approved products include fatty acid derivs. of human insulin or the glucagon-like-1 peptide (Levemir and Victoza) for treating diabetes, the taxol albumin nanoparticle Abraxane for treating metastatic breast cancer which is also under clin. investigation in further tumor indications, and 99mTc-aggregated albumin (Nanocoll and Albures) for diagnosing cancer and rheumatoid arthritis as well as for lymphoscintigraphy. In addn., an increasing no. of albumin-based or albumin-binding drugs are in clin. trials such as antibody fusion proteins (MM-111) for treating HER2/neu pos. breast cancer (phase I), a camelid albumin-binding nanobody anti-HSA-anti-TNF-α (ATN-103) in phase II studies for treating rheumatoid arthritis, an antidiabetic Exendin-4 analog bound to recombinant human albumin (phase I/II), a fluorescein-labeled albumin conjugate (AFL)-human serum albumin for visualizing the malignant borders of brain tumors for improved surgical resection, and finally an albumin-binding prodrug of doxorubicin (INNO-206) entering phase II studies against sarcoma and gastric cancer. In the preclin. setting, novel approaches include attaching peptides with high-affinity for albumin to antibody fragments, the exploitation of albumin-binding gadolinium contrast agents for magnetic resonance imaging, and phys. or covalent attachment of antiviral, antibacterial, and anticancer drugs to albumin that are permanently or transiently attached to human serum albumin (HSA) or act as albumin-binding prodrugs. This review gives an overview of the expanding field of preclin. and clin. drug applications and developments that use albumin as a protein carrier to improve the pharmacokinetic profile of the drug or to target the drug to the pathogenic site addressing diseases with unmet medical needs.
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    Schmidt, K.; Jung, M.; Keilitz, R.; Schnurr, B.; Gust, R. Acetylenehexacarbonyldicobalt complexes, a novel class of antitumor drugs. Inorg. Chim. Acta 2000, 306, 6– 16,  DOI: 10.1016/S0020-1693(00)00139-0

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    Acetylenehexacarbonyldicobalt complexes, a novel class of antitumor drugs

    Schmidt, K.; Jung, M.; Keilitz, R.; Schnurr, B.; Gust, R.

    Inorganica Chimica Acta (2000), 306 (1), 6-16CODEN: ICHAA3; ISSN:0020-1693. (Elsevier Science S.A.)

    Acetylenehexacarbonyldicobalt complexes were synthesized and tested for antitumor activity. The MCF-7 and MDA-MB-231 mammary tumor cell lines and the LNCaP/FGC prostate carcinoma cell line were used as in vitro models. The structural evaluation was performed by IR and NMR spectroscopy and revealed a change of the linear acetylene core to a structure comparable to Z-olefins after coordination to the cobalt centers. In cell culture expts. the strongest effects were found for hexacarbonyl[2-propinylacetylsalicylate]dicobalt, which was more active than cisplatin on the human mammary tumor cell lines MCF-7 and MDA-MB-231 in each concn. tested (a 5 μM concn. of this compd. even caused cytocidal effects). In contrast to this, hexacarbonyl[2-propinylacetylsalicylate]dicobalt influenced the growth of the LNCaP/FGC cells only marginally, even in the highest concn. The mode of action of the complexes tested is unknown. As the cobalt complexes show strong antiproliferative effects and their ligands do not it could be unambiguously demonstrated that complex formation is essential to achieve cytotoxic effects.
36. 36

    Provinciali, G.; Bortoluzzi, M.; Funaioli, T.; Zacchini, S.; Campanella, B.; Pampaloni, G.; Marchetti, F. Tetrasubstituted Selenophenes from the Stepwise Assembly of Molecular Fragments on a Diiron Frame and Final Cleavage of a Bridging Alkylidene. Inorg. Chem. 2020, 59, 17497– 17508,  DOI: 10.1021/acs.inorgchem.0c02748

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    Tetrasubstituted Selenophenes from the Stepwise Assembly of Molecular Fragments on a Diiron Frame and Final Cleavage of a Bridging Alkylidene

    Provinciali, Giacomo; Bortoluzzi, Marco; Funaioli, Tiziana; Zacchini, Stefano; Campanella, Beatrice; Pampaloni, Guido; Marchetti, Fabio

    Inorganic Chemistry (2020), 59 (23), 17497-17508CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)

    A series of 2,3-dicarboxylato-5-acetyl-4-aminoselenophenes 2,3-(R1O2C)2-4-Me2N-5-R2COC4Se (5a-j, R1 = Me, Et, tBu; R2 = Me, Et, n-Pr, Bu) was obtained via the uncommon assembly of building blocks on a diiron platform, starting from com. [Fe2Cp2(CO)4] through the stepwise formation of diiron complexes [2a-d]CF3SO3, 3a-d, and 4a-j. The selenophene-substituted bridging alkylidene ligand in 4a-j is removed from coordination upon treatment with water in air under mild conditions (ambient temp. in most cases), affording 5a-j in good to excellent yields. This process is highly selective and is accompanied by the disruption of the organometallic scaffold: cyclopentadiene (CpH) and lepidocrocite (γ-FeO(OH)) were identified by NMR and Raman analyses at the end of one representative reaction. The straightforward cleavage of the linkage between a bridging Fischer alkylidene and two (or more) metal centers, as obsd. here, is an unprecedented reaction in organometallic chem.: in the present case, the carbene function is converted to a ketone which is incorporated into the org. product. DFT calcns. and electrochem. expts. were carried out to give insight into the release of the selenophene-alkylidene ligand. Compds. 5a-j were fully characterized by elemental anal., mass spectrometry, IR, and multinuclear NMR spectroscopy and by X-ray diffraction and cyclic voltammetry in one case.
37. 37

    Agonigi, G.; Ciancaleoni, G.; Funaioli, T.; Zacchini, S.; Pineider, F.; Pinzino, C.; Pampaloni, G.; Zanotti, V.; Marchetti, F. Controlled Dissociation of Iron and Cyclopentadienyl from a Diiron Complex with a Bridging C₃ Ligand Triggered by One-Electron Reduction. Inorg. Chem. 2018, 57, 15172– 15186,  DOI: 10.1021/acs.inorgchem.8b02445

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    Controlled Dissociation of Iron and Cyclopentadienyl from a Diiron Complex with a Bridging C3 Ligand Triggered by One-Electron Reduction

    Agonigi, Gabriele; Ciancaleoni, Gianluca; Funaioli, Tiziana; Zacchini, Stefano; Pineider, Francesco; Pinzino, Calogero; Pampaloni, Guido; Zanotti, Valerio; Marchetti, Fabio

    Inorganic Chemistry (2018), 57 (24), 15172-15186CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)

    The one-electron redn. of a diiron cationic complex revealed unique features: cleavage of the diiron structure occurred despite a multidentate bridging C3 ligand and was accompanied by the clean dissocn. of one η5-cyclopentadienyl ring and one iron as isolated units. Thus, the iron(II)-iron(II) μ-vinyliminium complex [Fe2Cp2(CO)(μ-CO){μ-η1:η3-C3(Et)C2HC1N(Me)(Xyl)}][SO3CF3] ([1a]SO3CF3) reacted with cobaltocene in THF (THF), affording the iron(II) vinylaminoalkylidene [FeCp(CO){C1N(Me)(Xyl)C2HC3(Et)C(O)}] (2a) in 77% yield relative to the C3 ligand. Analogously, [FeCp(CO){C1N(Me)(Xyl)C2HC3(CH2OH)C(O)}] (2b) was obtained in 64% yield from the appropriate diiron precursor and CoCp2. The formation of 2a is initiated by the one-electron redn. of [1a]+, followed by a reversible intramol. rearrangement terminating with the irreversible release of CpH (NMR and gas chromatog.-mass spectrometry) and Fe [ESR (EPR) and magnetometry]. The key intermediate iron(I) ferraferrocene (3) was detected by EPR and IR spectroelectrochem., while the related species 3-H-3 was isolated after the addn. of a hydrogen source and then identified by X-ray diffraction. A plausible mechanism for the route from [1a]+ to 3 was ascertained by d. functional theory calcns. The dication [1a]2+, displaying both carbonyl ligands in terminal positions, and the anion [3]- were electrochem. generated. The functionalized diiron compds. 4 (52% yield) and 5 (62%) were afforded through the activation of O2 and S8 by a radical intermediate along the reductive pathway of [1a]+. The reaction of [Fe2Cp2(CO)(μ-CO){μ-η1:η3-C(SiMe3)CHCN(Me)(Xyl)}][SO3CF3] ([1c]SO3CF3) with CoCp2 in THF afforded [Fe2Cp2(C≡CSiMe3)(CO)(μ-CO){μ-CNMe(Xyl)}] (6) in 65% yield.
38. 38

    Menges, F. Spectragryph - optical spectroscopy software, Ver. 1.2.5 , 2016–2017; http://www.effemm2.de/spectragryph.

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    There is no corresponding record for this reference.
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    Fulmer, G. R.; Miller, A. J. M.; Sherden, N. H.; Gottlieb, H. E.; Nudelman, A.; Stoltz, B. M.; Bercaw, J. E.; Goldberg, K. I. NMR Chemical Shifts of Trace Impurities: Common Laboratory Solvents, Organics, and Gases in Deuterated Solvents Relevant to the Organometallic Chemist. Organometallics 2010, 29, 2176– 2179,  DOI: 10.1021/om100106e

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    39

    NMR Chemical Shifts of Trace Impurities: Common Laboratory Solvents, Organics, and Gases in Deuterated Solvents Relevant to the Organometallic Chemist

    Fulmer, Gregory R.; Miller, Alexander J. M.; Sherden, Nathaniel H.; Gottlieb, Hugo E.; Nudelman, Abraham; Stoltz, Brian M.; Bercaw, John E.; Goldberg, Karen I.

    Organometallics (2010), 29 (9), 2176-2179CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)

    Tables of 1H and 13C NMR chem. shifts have been compiled for common org. compds. often used as reagents or found as products or contaminants in deuterated org. solvents. Building upon the work of Gottlieb, Kotlyar, and Nudelman in the Journal of Org. Chem., signals for common impurities are now reported in addnl. NMR solvents (tetrahydrofuran-d8, toluene-d8, dichloromethane-d2, chlorobenzene-d5, and 2,2,2-trifluoroethanol-d3) which are frequently used in organometallic labs. Chem. shifts for other orgs. which are often used as reagents or internal stds. or are found as products in organometallic chem. are also reported for all the listed solvents.
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    Willker, W.; Leibfritz, D.; Kerssebaum, R.; Bermel, W. Gradient selection in inverse heteronuclear correlation spectroscopy. Magn. Reson. Chem. 1993, 31, 287– 292,  DOI: 10.1002/mrc.1260310315

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    Gradient selection in inverse heteronuclear correlation spectroscopy

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    Magnetic Resonance in Chemistry (1993), 31 (3), 287-92CODEN: MRCHEG; ISSN:0749-1581.

    After a brief theor. description, new gradient-selected (gs), proton-detected heteronuclear correlation sequences are introduced. The gs-HMBC (heteronuclear multiple bond correlation) and gs-relayed-HMQC are closely related to the original gs-HMQC proposed by Hurd and John. A new approach to obtain pure absorption line shapes in gradient selected spectroscopy is used to measure phase-sensitive gs-HMQC spectra, to carry out multiplicity editing in HSQC spectra and to distinguish direct and long-range correlations in HMQC/HSQC-TOCSY spectra.
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    Albano, V. G.; Busetto, L.; Monari, M.; Zanotti, V. Reactions of acetonitrile di-iron μ-aminocarbyne complexes; synthesis and structure of [Fe₂(μ-CNMe₂)(μ-H)(CO)₂(Cp)₂]. J. Organomet. Chem. 2000, 606, 163– 168,  DOI: 10.1016/S0022-328X(00)00337-5

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    Reactions of acetonitrile di-iron μ-aminocarbyne complexes; synthesis and structure of [Fe2(μ-CNMe2)(μ-H)(CO)2(Cp)2]

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    Journal of Organometallic Chemistry (2000), 606 (2), 163-168CODEN: JORCAI; ISSN:0022-328X. (Elsevier Science S.A.)

    [Fe2{μ-CN(Me)R}(μ-CO)(NCMe)(CO)(Cp)2]SO3CF3 (R = Me, 2a; 2,6-Me2C6H3, 2b; CH2Ph, 2c), easily obtained from the corresponding [Fe2{μ-CN(Me)R}(μ-CO)(CO)2(Cp)2]SO3CF3 (1a-c) precursors, react with NBu4CN affording the cyano complexes [Fe2{μ-CN(Me)R}(μ-CO)(CN)(CO)(Cp)2] (3a-c) by displacement of the MeCN ligand. The analogous reaction with NBu4Cl gives [Fe2{μ-CN(Me)R}(μ-CO)(Cl)(CO)(Cp)2] (4a-b). The μ-hydride complexes [Fe2{μ-CN(Me)R}(μ-H)(CO)2(Cp)2] (5a-b) were prepd. by reaction of 1a-b with NaBH4. The corresponding diruthenium compd. [Ru(μ-CNMe)2(μ-H)(CO)2(Cp)2] (6) was similarly obtained from [Ru2(μ-CNMe)2(μ-CO)(NCMe)(CO)(Cp)2]SO3CF3. The x-ray mol. structure of 5a is that expected for cis isomers of this family of compds. It shows a chiral conformation of the C5H5 ligands and the crystals are a conglomerate of enantiomeric individuals. NMR spectra of the various compds., which are indicative of the presence of α-β or cis-trans isomeric mixts., are reported and discussed.
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    Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods 1983, 65, 55– 63,  DOI: 10.1016/0022-1759(83)90303-4

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    Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays

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    Journal of immunological methods (1983), 65 (1-2), 55-63 ISSN:0022-1759.

    A tetrazolium salt has been used to develop a quantitative colorimetric assay for mammalian cell survival and proliferation. The assay detects living, but not dead cells and the signal generated is dependent on the degree of activation of the cells. This method can therefore be used to measure cytotoxicity, proliferation or activation. The results can be read on a multiwell scanning spectrophotometer (ELISA reader) and show a high degree of precision. No washing steps are used in the assay. The main advantages of the colorimetric assay are its rapidity and precision, and the lack of any radioisotope. We have used the assay to measure proliferative lymphokines, mitogen stimulations and complement-mediated lysis.
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    Rosenkranz, A. R.; Schmaldienst, S.; Stuhlmeier, K. M.; Chen, W.; Knapp, W.; Zlabinger, G. J. A microplate assay for the detection of oxidative products using 2’,7’-dichlorofluorescin-diacetate. J. Immunol. Methods 1992, 156, 39– 45,  DOI: 10.1016/0022-1759(92)90008-H

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    A microplate assay for the detection of oxidative products using 2',7'-dichlorofluorescin-diacetate

    Rosenkranz, Alexander R.; Schmaldienst, Sabine; Stuhlmeier, Karl M.; Chen, Wanjun; Knapp, Walter; Zlabinger, Gerhard J.

    Journal of Immunological Methods (1992), 156 (1), 39-45CODEN: JIMMBG; ISSN:0022-1759.

    A fluorometric microplate assay was established for the detection of respiratory burst activity in phagocytic cells by assessing oxidn. of 2',7'-dichlorofluorescin-diacetate (DCFH-DA). This method is based on flow cytometric studies by D. A. Bass et al. (1983) describing intracellular detection of DCFH oxidn. due to the presence of hydrogen peroxides. Here, the assay was adapted for use in microtiter plates to det. the amt. of extracellular reactive oxidative products. DCFH-DA, granulocytes and stimuli (phorbol myristate acetate, N-formyl-Met-Leu-Phe, Con A) were added to microtiter plates and after incubation at 37°, the development of fluorescence intensity was read in a fluorescence concn. analyzer (FCA, Baxter). Calibration of fluorescence units recorded by the FCA was achieved by comparison with defined amts. of fluorescent DCF. The change in measured fluorescence was linear with cell d. over the range of 2×105-1×106 cells/well. Cumulative DCF generation in individual wells could be recorded nondestructively at frequent intervals for time course measurements. Results from FCA measurements correlated perfectly with the FACS anal. of the same samples. In conclusion, this assay can be useful for screening monoclonal antibodies recognizing cell surface structures possibly involved in signal transduction as well as for testing phagocytes for their capacity to release reactive oxidative intermediates.