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Synthesis of Triazole-Substituted Quinazoline Hybrids for Anticancer Activity and a Lead Compound as the EGFR Blocker and ROS Inducer AgentClick to copy article linkArticle link copied!
- Biswadip Banerji*Biswadip Banerji*E-mail: [email protected], [email protected]. Phone: +91 33 24995709. Fax: +91 33 24735197, +91 33 24723967.Organic & Medicinal Chemistry Division and Academy of Scientific and Innovative Research (AcSIR), Indian Institute of Chemical Biology (CSIR-IICB), 4 Raja S. C. Mullick Road, Kolkata 700032, IndiaMore by Biswadip Banerji
- Kadaiahgari ChandrasekharKadaiahgari ChandrasekharOrganic & Medicinal Chemistry Division and Academy of Scientific and Innovative Research (AcSIR), Indian Institute of Chemical Biology (CSIR-IICB), 4 Raja S. C. Mullick Road, Kolkata 700032, IndiaMore by Kadaiahgari Chandrasekhar
- Kancham SreenathKancham SreenathNational Institute of Pharmaceutical Education and Research (NIPER)—Kolkata, 4, Raja S. C. Mullick Road, Kolkata 700032, IndiaMore by Kancham Sreenath
- Saheli RoySaheli RoyCancer Biology & Inflammatory Disorder, Indian Institute of Chemical Biology (CSIR-IICB), 4 Raja S. C. Mullick Road, Kolkata 700032, IndiaMore by Saheli Roy
- Sayoni NagSayoni NagCancer Biology & Inflammatory Disorder, Indian Institute of Chemical Biology (CSIR-IICB), 4 Raja S. C. Mullick Road, Kolkata 700032, IndiaMore by Sayoni Nag
- Krishna Das SahaKrishna Das SahaCancer Biology & Inflammatory Disorder, Indian Institute of Chemical Biology (CSIR-IICB), 4 Raja S. C. Mullick Road, Kolkata 700032, IndiaMore by Krishna Das Saha
Abstract
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A series of triazole-substituted quinazoline hybrid compounds were designed and synthesized for anticancer activity targeting epidermal growth factor receptor (EGFR) tyrosine kinase. Most of the compounds showed moderate to good antiproliferative activity against four cancer cell lines (HepG2, HCT116, MCF-7, and PC-3). Compound 5b showed good antiproliferative activity (IC50 = 20.71 μM) against MCF-7 cell lines. Molecular docking results showed that compound 5b formed hydrogen bond with Met 769 and Lys 721 and π–sulfur interaction with Met 742 of EGFR tyrosine kinase (PDB ID: 1M17). Compound 5b decreases the expression of EGFR and p-EGFR. It also induces apoptosis through reactive oxygen species generation, followed by the change in mitochondrial membrane potential.
Copyright © 2018 American Chemical Society
Introduction
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Cancer is one of the most devastating diseases in the developing countries. (1) The epidermal growth factor receptor (EGFR) plays an important role in cell survival, growth, differentiation, and tumorigenesis. Dysregulation of EGFR is a common mechanism in cancer progression especially in nonsmall cell lung cancer (NSCLC). Also, overexpression of EGFR has been observed in different types of cancers such as breast, ovarian, head and neck, colon, and so forth. (2) Some FDA-approved drugs, EGFR inhibitors such as erlotinib (3) (i), gefitinib (4) (ii), icotinib (5) (iii), lapatinib (6) (iv), and afatinib (7) (v), are used for the treatment of the above-mentioned cancers (Figure 1). The interplay of reactive oxygen species (ROS) and the EGFR plays an important role in cancer progression. Excessive ROS can induce negative responses such as growth inhibition or death of cancer cells. Mitochondrial dysfunction is also the major mechanism inducing oxidative stress. Higher ROS levels can trigger overoxidation of the Met residue of EGFR T790M and shut down the EGFR downstream survival pathway. (8) Therefore, direct EGFR inhibition or inhibition of EGFR function via excessive ROS generation or both may be a feasible therapeutic approach for cancer treatment.
Figure 1
Figure 1. Chemical structure of some reported anticancer agents.
Side effects are major problems with the current EGFR inhibiting anticancer drugs. For example, erlotinib significantly reduced the levels of white blood cells, red blood cells (RBCs), and hemoglobin. It increased liver function markers, aspartate aminotransferase and alanine aminotransferase levels, and damaged the internal organs in an experimental rat model. (9) Similarly, unusual hematologic complications were detected after erlotinib was administered in patients with advanced NSCLC. (10) Therefore, it is important to design new EGFR inhibitors as anticancer agents with low toxicity on normal organs and blood cells.
Quinazoline is an important heterocyclic moiety used in drug discovery because of its diverse biological activities. (11) Especially, 4-aminoquinazoline moiety showed good efficacy against various cancers. The structure–activity relationship (SAR) of EGFR inhibitors such as erlotinib and lapatinib revealed a quinazoline moiety to play an important role in antitumor activity, especially 4-aminoquinazoline moiety. 4-Aminoquinazoline moiety seemed particularly very important for activity and showed diverse biological activities such as anticancer, (12) antitubercular, (13) antimalarial, (14) antileishmanial, (15) and antibacterial and antifungal activities. (16)
1,2,3-Triazole is another important pharmacophore in medicinal chemistry and it can form hydrogen bonding with biological targets, (17) which will be useful for the activity. Also, triazole moiety-containing molecules (vi–ix, Figure 1) are known to show various pharmacological activities such as anticancer, (18) anti-human immunodeficiency virus, (19) antitubercular, (20) and anti-inflammatory (21) activities. These structural features and importance in various biological activities have made this moiety very important in drug discovery. The fight against cancer and hence the research to cure the disease are continuing since last many years. Many novel therapeutics were tried, but most of them suffer from severe toxicities. In an ongoing project in our laboratory on the discovery of new anticancer agents, (22) we were interested to make EGFR inhibitors. Recently, molecular hybridization approach has been widely used for the design and synthesis of small hybrid compounds for the treatment of cancer. The approach mainly involves combining two or more different pharmacophore moieties in a single molecule having a common scaffold. These hybrid molecules have many advantages over the conventional drugs such as toxicity, (23) solubility, multidrug resistance, and so forth. In the present study, we are using the molecular hybridization strategy to combine the biologically important two scaffolds, quinazoline and 1,2,3-triazole, to get a small set of new hybrid compounds (Figure 2). As discussed earlier, both quinazoline and 1,2,3-triazole moieties are very important for the anticancer activity, thus we synthesized 20 triazole-containing quinazoline hybrid compounds and performed cytotoxicity studies and the molecular docking studies thereafter. A lead compound was used to study EGFR inhibition, ROS generation, and toxicity in normal cells as well as in blood cells.
Figure 2
Figure 2. Design strategy of the target molecule.
Results and Discussion
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The synthesis was started by converting 4-nitro-benzylbromide 1 to the corresponding azide 2 in the presence of sodium azide in tetrahydrofuran (THF)–water in 95% yield. Compound 2 was reacted with different mono-substituted alkynes under classical “click” condition to produce different triazole compounds 3 in good yields. Finally, nitro group in 3 was reduced (Fe/NH4Cl in ethanol and water) to the corresponding amine 4, which was further coupled with different 4-chloro quinazolines to give the desired target compounds (5a–5t) in 73–88% yield (Scheme 1). All compounds were fully characterized by 1H nuclear magnetic resonance (NMR), 13C NMR, Fourier transform infrared (FT-IR), and high-resolution mass spectrometry (HRMS) data.
Scheme 1
Scheme 1. Synthetic Route of the Target Molecule and Crystal Structure of Compound 5c (ccdc: 1854806)a
aReagents and conditions: (a) NaN3, THF/H2O (4:1), RT, 1 h, 95%; (b) CuI, THF, different alkynes, reflux, 80 °C, 3 h, 80–85%; (c) Fe, NH4Cl, EtOH/H2O (1:1), reflux, 80 °C, 2 h, 76–80%; (d) NaOAc, THF/H2O (4:1), different quinazolines, reflux, 80 °C, 6 h, 73–88%.
The average 50% inhibitory concentration (IC50) values (concentration needed to inhibit cancer cell line proliferation by 50%) of the compounds (5a–5t) against four human cancer cell lines that include HCT116 (human colorectal cancer cell line), HEPG2 (human liver cancer cell line), MCF-7 (human breast cancer cell line), and PC-3 (human prostate cancer cell line) were determined using the cytotoxicity assay method. The IC50 values are listed in Table 1, and the marketed anticancer drug erlotinib was used as positive control. On the basis of the cytotoxicity assay results, further efforts were made to elucidate the SAR. All of the synthesized compounds were screened against different cancer cell lines (HepG2, MCF-7, HCT116, and PC-3). Results suggested that most of the compounds showed moderate to good efficacy toward MCF-7 compared to other cell lines. Among all, compound 5b showed the best activity with an IC50 value of 20.71 μM in MCF-7 cell lines. Moreover, it was observed that compounds bearing the −Cl atom at the second position of quinazoline (5b, 5e, 5h, 5k, and 5n) were better compared to other substitutions. Surprisingly, all of the above-mentioned active compounds containing −OMe group at the 6, 7 position of the quinazoline moiety are resulted, strongly suggesting that the chlorine atom at the 2nd position and −OMe group at the 6, 7 position of quinazoline are necessary for the activity.
Table 1. Cytotoxicity Activities of Compounds 5a–5t against HepG2, MCF-7, HCT116, and PC-3 in Micromolar
The best compound 5b has an IC50 value of 20.71 μM, which is higher than the standard compound erlotinib (11.57 μM). Interestingly, 5b also shows lower toxicity than erlotinib on a normal human epithelial kidney cell line (40.32 ± 4.43 and 29.48 ± 3.32 μM), in human blood RBC (45.6 ± 2.65 and 16.23 ± 3.23 μM), and in human peripheral blood mononuclear cell (37.38 ± 3.55 and 20.46 ± 4.1 μM, respectively). Therefore, though compound 5b shows relatively low toxicity than erlotinib in cancer cells, it has low toxicity in normal cell lines and normal blood cells. Thus, compound 5b is expected to be a better drug candidate than erlotinib. Gratifyingly, compound 5b also has 4-amino quinazoline moiety as the pharmacophore similar to that of erlotinib and gefitinib, and we thought that compound 5b shows anticancer activity through the EGFR-mediated pathway. For this study, we selected the crystal structure (PDB ID: 1M17) (24) of EGFR tyrosine kinase for the molecular modeling study. To study the interaction between EGFR tyrosine kinase and triazole-substituted quinazoline hybrid derivatives, molecular docking of the EGFR protein (PDB ID: 1M17) and compound 5b using discovery studio software was performed. Discovery studio was used for the visualization of interaction of the target molecule with EGFR tyrosine kinase. Docking results showed that compound 5b goes and binds in the adenosine 5′-triphosphate (ATP)-binding pocket of 1M17 and showed two hydrogen bonding interactions with N1 of quinazoline with the main-chain NH group of Met 769 at a distance of 3.13 Å and triazole N2 with Lys 721 in the ATP-binding pocket at a distance of 3.04 Å. Both erlotinib and compound 5b go and bind in the same ATP-binding pocket of EGFR tyrosine kinase (1M17, Figure 3).
Figure 3
Figure 3. (a) Surface representation of the EGFR protein (PDB ID 1M17) along with compound 5b (magenta) and erlotinib (blue). (b,c) Three-dimensional (3D) and two-dimensional (2D) representation of molecular docking interactions of compound 5b in the ATP-binding pocket of EGFR tyrosine kinase (1M17). (d,e) 3D and 2D molecular docking interactions of erlotinib in the ATP-binding pocket of EGFR tyrosine kinase.
Compound 5b also showed other interactions such as halogen interaction with Gln 767, π–alkyl interaction with Leu 694, Leu 820, and Cys 751, and π–sulfur interaction with Met 742. Erlotinib was used as the reference compound, which also formed a similar H-bond with Met 769 at a distance of 2.85 Å.
EGFR is an important signaling network in the case of cell proliferation, adhesion, migration, and survival. In order to study the mechanism of triazole-substituted quinazoline hybrids, we investigated the effect of compound 5b on the EGFR signaling pathway in MCF-7 cell lines using western blot analysis. (25) After treatment with compound 5b in MCF-7 cell lines, the level of EGFR and p-EGFR decreases with different time intervals of 12 and 24 h (Figure 4). In this experiment, erlotinib was used as positive control. These results confirmed that the antiproliferative effect of compound 5b in MCF-7 cell lines is mainly due to the decrease of EGFR and phosphorylation of EGFR and its downstream process. EGFR inhibition leads to the activation of ROS generation, which leads to DNA damage and cell death. Cellular generation of ROS is an important factor of apoptotic cell death. We have examined here the status of ROS generation by compound 5b. The maximum ROS generation was observed at 24 h after the treatment of MCF-7 cells with compound 5b. Also, flow cytometric analysis revealed that the fluorescein isothiocyanate (FITC) mean intensity was 765 in control cells but 1683 in compound 5b (20.71 μM) treated cells after 24 h, indicating a shift in FITC mean intensity from the control cells to the cells treated with compound 5b. These results demonstrated that compound 5b (20.71 μM) inducing apoptosis in MCF-7 cells at 12 and 24 h might proceed via the ROS-mediated pathway. (26)
Figure 4
Figure 4. Western blot image of expression of EGFR and p-EGFR upon treatment with compound 5b and erlotinib (positive control).
Apoptosis is the desired way of cancer cell death. To determine the effect of compound 5b on apoptosis, fluorescence-activated cell sorting (FACS) was performed on MCF-7 cell lines treated with compound 5b at different time intervals. (27) At the initial stage of apoptosis, phosphatidyl serine is exposed from inside cell membrane to outside and this can bind with annexin V. After treatment of MCF-7 cells with compound 5b (20.71 μM) at time points (0, 12, and 24 h), MCF-7 cells were stained with annexin V-FITC and propidium iodide (PI) and monitored by flow cytometry. It was observed that early apoptosis rates increased from 5.9 to 24.6% and the late apoptosis rates increased from 0.7 to 14.2%. The results showed that compound 5b increased cellular apoptosis in a time-dependent manner (Figure 5). Flow cytometric analysis of control cells revealed that 84.4% of the cell population exhibited fluorescence at the PE-Texas Red A channel, indicating a higher level of cells having a healthy ΔΨm, whereas compound 5b (20.71 μM) treated cells at 24 h revealed that 29.5% of the cell population exhibited fluorescence at the PE-Texas Red A channel, which showed a loss of ΔΨm in 54.9% of cell population after 24 h. (28) These results indicate that compound 5b might induce apoptosis by generation of ROS via the mitochondrial pathway as it leads to lowering of mitochondrial membrane potential.
Figure 5
Figure 5. Effect of compound 5b in (i) apoptosis induction through ROS generation, (ii) analysis of apoptosis, and (iii) apoptosis induction through the mitochondrial membrane potential assay in MCF-7 cells at different time points (0–24) h.
Conclusions
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In conclusion, a series of triazole-substituted quinazoline hybrid molecules were designed and synthesized as anticancer agents. The results showed that most of the compounds had moderate to good antiproliferative effects against four different cell lines HCT116, HepG2, PC-3, and MCF-7. Among them, compound 5b showed good antiproliferative effects against MCF-7 cell lines. Molecular docking studies showed that compound 5b formed hydrogen bond with Met 769 of the EGFR protein, which regulates the conformation of EGFR which is responsible for antiproliferative activity. Compound 5b decreased the expression of EGFR and p-EGFR in MCF-7 cell lines, from which we can conclude that compound 5b exhibits antiproliferative effects in MCF-7 cell lines through the EGFR signaling pathway. Compound 5b also caused change in mitochondrial membrane potential and ROS-mediated apoptosis in MCF-7 cell lines. From the above results, it may be concluded that compound 5b acts as the EGFR inhibitor and can be used in the treatment of cancer. Further optimization of the structure to show improved EGFR inhibitory and antiproliferative activity is ongoing in the laboratory.
Experimental Section
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General Remarks
All chemicals and reagents were purchased from Sigma-Aldrich. Column chromatography purifications were performed using silica gel grade 9385, 100–200 mesh, neutral alumina (Sigma). Thin-layer chromatography (TLC) was performed on silica gel 60 F254 plates with 0.20 mm thickness (Merck, Germany), which was visualized under an ultraviolet light chamber (254 and 365 nm). NMR experiments were run on Bruker Avance III 600 (600 MHz for 1H and 150 MHz for 13C). 1H NMR spectra were recorded for solution in CDCl3 or dimethyl sulfoxide (DMSO) with tetramethylsilane as the standard. Chemical shifts for 1H and 13C spectra were recorded in parts per million (ppm). Data were reported as follows: chemical shift (ppm), integrated intensity, multiplicity (indicated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), and coupling constants (J) in hertz (Hz). HRMS spectra were obtained on a JEOL MS station 700 (JEOL Ltd., Akishima-Shi, Japan). The FT-IR spectra of the samples were recorded on a JASCO FT-IR 4200 spectrometer (JASCO, Easton, MD, USA) using a KBr disk technique. The spectra were recorded from 400 to 4000 cm–1. JASCO software was used for data processing. Apoptosis, ROS, and JC1 assay were performed by FACSCalibur flow cytometry (Becton Dickinson, San Jose, CA, USA).
Synthetic Procedure
General Procedure To Synthesize Compound 2
To the solution of compound 1 (1 equiv) in THF was added sodium azide (1.5 equiv) which was dissolved in water dropwise at 0 °C. The reaction mixture was then stirred for 1 h (0 °C to rt) and was monitored through TLC. After the complete consumption of the starting material, the solvent was evaporated. The crude mixture was then dissolved in EtOAc and washed with water and brine (3 × 10 mL). Thereafter, the organic layer was collected and dried over Na2SO4 and concentrated under reduced pressure to get yellow liquid in 95% yield.
General Procedure To Synthesize Compound 3
To the solution of compound 2 (1 equiv) in THF were added different acetylene (1 equiv) and copper iodide (0.2 equiv), which was heated to reflux temperature (80 °C) for 3 h. After the total consumption of the starting material (monitored through TLC), the solvent was evaporated. The reaction mixture was then diluted with ethyl acetate, filtered through a Celite bed, and washed with water and brine (3 × 10 mL) in a separating funnel. Thereafter, the organic layer was collected and dried over Na2SO4 and then evaporated under reduced pressure to get a crude solid, which was purified by column chromatography (silica gel 100–200, per ether/ethyl acetate 4:1) to afford the desired product as yellow solid with 80–85% yield.
General Procedure To Synthesize Compound 4
To the solution of compound 3 (1 equiv) in ethanol–water (1:1) were added iron powder (4 equiv) and ammonium chloride (10 equiv), which was heated to reflux temperature (80 °C) for 2 h. The reaction was monitored through TLC until total consumption of the starting material. After completion, ethanol was evaporated, and the crude mixture was diluted with ethyl acetate and passed through a Celite bed. Then, it was washed with water and brine (3 × 10 mL) in a separating funnel. Thereafter, the organic layer was collected and dried over Na2SO4 and evaporated under reduced pressure to get the crude solid. It was then purified by column chromatography (silica gel 100–200, per ether/ethyl acetate 1.5:1) to afford the desired product as yellow solid with 76–80% yield.
General Procedure To Synthesize Compound 5
To the solution of compound 4 (1 equiv) in THF/water (4:1), different substituted 4-chloro quinazoline (0.9 equiv) and anhydrous sodium acetate (3 equiv) were added. The reaction mixture was heated to reflux temperature (80 °C) for 6 h and monitored through TLC. After total consumption of the starting material, the solvent was evaporated. The residue was then dissolved in EtOAc and washed with water and brine (3 × 10 mL). The organic layer was thereafter collected and dried over Na2SO4. It was then purified by column chromatography (neutral aluminum oxide, dichloromethane/methanol 49:1) to afford the desired product in 73–88% yield as a white powder.
In similar manner, all other triazole-containing quinazoline hybrid compounds (5a–5t) were prepared.
Characterization Data
6,7-Dimethoxy-N-(4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)quinazolin-4-amine (5a)
Yield 87% (32 mg); pale yellow solid; mp: 220–221 °C; 1H NMR (600 MHz, DMSO-d6): δ 9.53 (s, 1H), 8.65 (s, 1H), 8.44 (s, 1H), 7.86 (d, J = 7.8 Hz, 2H), 7.82 (m, 3H), 7.44 (t, J = 6 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H), 7.18 (s, 1H), 5.63 (s, 2H), 3.95 (s, 3H), 3.92 (s, 3H). 13C NMR (150 MHz, DMSO-d6): δ (ppm) 156.7, 154.7, 153.2, 149.3, 147.4, 147.1, 139.9, 131.1, 129.3, 128.7, 128.3, 125.6, 122.9, 121.8, 109.3, 107.6, 100.3, 56.6, 56.2, 53.2. IR (KBr) [cm–1] ν: 3386, 3314, 3201, 3138, 3007, 1624, 1577, 1517, 1467, 1426, 1351, 1245, 1146, 1070.41, 993, 923, 855, 763, 691, 657. HRMS (ESI-m/z): calcd for C25H22N6O2, [M + H]+ 439.1822; found, 439.1892.
2-Chloro-6,7-dimethoxy-N-(4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)quinazolin-4-amine (5b)
Yield 82% (37 mg); white solid; mp: 292–293 °C; 1H NMR (600 MHz, DMSO-d6): δ 9.90 (s, 1H), 8.68 (s, 1H), 7.86 (d, J = 7.2 Hz, 3H), 7.74 (d, J = 8.4 Hz, 2H), 7.43 (m, 4H), 7.33 (t, J = 7.2 Hz, 1H), 7.17 (s, 1H), 5.66 (s, 2H), 3.94 (s, 3H), 3.92 (s, 3H). 13C NMR (150 MHz, DMSO-d6): δ 157.9, 155.0, 154.2, 149.0, 148.2, 146.6, 138.4, 131.7, 130.7, 128.9, 128.3, 127.9, 125.2, 122.9, 121.5, 107.2, 106.6, 102.2, 56.3, 56.0, 52.7. IR (KBr) [cm–1] ν: 3361, 3138, 2988, 2948, 1621, 1572, 1515, 1458, 1426, 1240, 1150, 1001, 963, 842, 763, 697. HRMS [EI-m/z]: calcd for C25H21N6O2Cl, [M]+ 472.1415; found, 472.14136.
N-(4-((4-Phenyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)quinazolin-4-amine (5c)
Yield 85% (30 mg); white solid; mp: 270–271 °C; 1H NMR (600 MHz,, DMSO-d6): δ 9.85 (s, 1H), 8.66 (s, 1H), 8.58 (s, 1H), 8.55 (d, J = 8.4 Hz, 1H), 7.87 (m, 5H), 7.79 (d, J = 8.4 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.42 (m, 4H), 7.33 (t, J = 7.2 Hz, 1H), 5.64 (s, 2H). 13C NMR (150 MHz, DMSO-d6): δ 158.1, 154.8, 150.1, 147.1, 139.6, 133.5, 131.5, 131.1, 129.3, 128.7, 128.3, 128.2, 126.7, 125.6, 123.4, 123.0, 121.8, 115.6, 53.2. IR (KBr) [cm–1] ν: 3258, 3135.49, 3087, 1611, 1570, 1524, 1501, 1415, 1357, 1224, 1074, 1043, 922.80, 766, 683, 511. HRMS [EI-m/z]: calcd for C23H18N6, [M]+ 378.1593; found, 378.15329.
N-(4-((4-(4-Ethylphenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-6,7-dimethoxyquinazolin-4-amine (5d)
Yield 88% (39 mg); white solid; mp: 230–231 °C; 1H NMR (600 MHz, CDCl3): δ 8.68 (s, 1H), 8.06 (d, J = 12 Hz, 1H) 7.71 (s, 1H), 7.68 (m, 4H), 7.43 (d, J = 6 Hz, 1H), 7.27 (s, 1H), 7.22 (m, 4H), 5.55 (s, 2H), 4.03 (s, 3H), 3.92 (d, J = 1.8 Hz, 3H), 2.65 (q, J = 7.8 Hz, 2H), 1.23 (t, J = 7.8 Hz, 3H). 13C NMR (150 MHz, CDCl3): δ 156.4, 154.7, 153.4, 149.6, 148.5, 147.5, 144.6, 139.3, 138.9, 129.9, 128.5, 128.4, 127.5, 125.6, 122.3, 119.6, 109.3, 107.7, 99.9, 56.3, 56.2, 53.8, 28.6, 15.4. IR (KBr) [cm–1] ν: 3379, 2956, 1623, 1577, 1516, 1462, 1423, 1394, 1240, 1140, 1061, 996, 840, 798, 540. HRMS (ESI-m/z): calcd for C27H26N6O2, [M + H]+ 466.2195; found, 467.2189.
2-Chloro-N-(4-((4-(4-ethylphenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-6,7-dimethoxyquinazolin-4-amine (5e)
Yield 84% (34 mg); white solid; mp: 277–278 °C; 1H NMR (600 MHz, DMSO-d6): δ 9.89 (s, 1H), 8.61 (s, 1H), 7.85 (s, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.16 (s, 1H), 5.64 (s, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 2.61 (q, J = 7.8, 2H), 1.19 (t, J = 7.8, 3H). 13C NMR (150 MHz, DMSO-d6): δ 158.3, 155.4, 154.6, 149.5, 148.6, 147.2, 143.9, 138.9, 132.2, 128.7, 125.6, 123.4, 121.6, 107.7, 107.1, 102.6, 56.7, 56.4, 53.1, 28.3, 15.9. IR (KBr) [cm–1] ν: 3356, 2965, 1621, 1573, 1515, 1455, 1427, 1343, 1294, 1240, 1150, 1002, 962, 839, 800, 580, 530. HRMS [EI-m/z] calcd for C27H25N6O2Cl, [M]+ 500.1728; found, 500.17178.
N-(4-((4-(4-Ethylphenyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)quinazolin-4-amine (5f)
Yield 87% (28 mg); white solid; mp: 250–251 °C; 1H NMR (600 MHz,, DMSO-d6): δ 9.86 (s, 1H), 8.59 (d, J = 6 Hz, 2H), 8.54 (d, J = 12 Hz, 1H), 7.88 (d, J = 6 Hz, 2H), 7.85 (d, J = 6 Hz, 1H), 7.79 (d, J = 12 Hz, 1H), 7.76 (d, J = 12 Hz, 2H), 7.64 (t, J = 12 Hz, 1H), 7.41 (d, J = 6 Hz, 2H), 7.27 (d, J = 7.8 Hz, 2H), 5.62 (s, 2H), 2.61 (q, J = 7.8 Hz, 2H), 1.19 (t, J = 7.8 Hz, 3H). 13C NMR (150 MHz, DMSO-d6): δ 158.2, 154.8, 150.1, 147.2, 143.9, 139.5, 133.5, 131.6, 128.7, 128.7, 128.6, 128.2, 126.7, 125.6, 123.4, 123.0, 121.4, 115.6, 53.2, 28.3, 15.9. IR (KBr) [cm–1] ν: 3422, 3290, 3103, 2967, 2927, 1616, 1571, 1526, 1498, 1422, 1358, 1319, 1224, 1049, 924, 830, 770, 677. HRMS [EI-m/z] calcd for C25H22N6, [M]+ 406.1915; found, 406.19156.
(1-(4-(6,7-Dimethoxyquinazolin-4-ylamino)benzyl)-1H-1,2,3-triazol-4-yl)methanol (5g)
Yield 77% (29 mg); off-white solid; mp: 295–296 °C; 1H NMR (600 MHz,, DMSO-d6): δ 9.52 (s, 1H), 8.43 (s, 1H), 8.02 (s, 1H), 7.82 (s, 1H), 7.77 (d, J = 7.8 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.18 (s, 1H), 5.55 (s, 2H), 5.18 (t, J = 5.4 Hz, 1H), 4.51 (d, J = 6 Hz, 2H), 3.95 (s, 3H), 3.92 (s, 3H). 13C NMR (150 MHz, DMSO-d6): δ 156.7, 154.7, 153.2, 149.3, 148.7, 147.4, 131.3, 128.7, 123.1, 122.9, 109.3, 107.6, 102.3, 56.6, 56.2, 55.5, 52.9. IR (KBr) [cm–1] ν: 3315, 3146, 3004.33, 2928, 2834, 1623, 1579, 1517, 1466, 1425, 1246, 1140, 1050, 994, 924, 854, 779, 657, 557, 515. HRMS (ESI-m/z) calcd for C20H20N6O3, [M + H]+ 392.1675; found, 393.1675.
(1-(4-(2-Chloro-6,7-dimethoxyquinazolin-4-ylamino)benzyl)-1H-1,2,3-triazol-4-yl)methanol (5h)
Yield 74% (24 mg); light yellow solid; mp: 265–266 °C; 1H NMR (600 MHz,, DMSO-d6): δ 9.89 (s, 1H), 8.04 (s, 1H), 7.85 (s, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.17 (s, 1H), 5.57 (s, 2H), 5.20 (s, 1H), 4.51 (s, 2H), 3.94 (s, 3H), 3.92 (s, 3H). 13C NMR (150 MHz, DMSO-d6): δ 158.4, 155.4, 154.6, 149.5, 148.8, 148.6, 138.7, 132.4, 128.8, 123.4, 107.06, 107.04, 102.6, 56.7, 56.4, 55.5, 52.8. IR (KBr) [cm–1] ν: 3390, 3282, 3037, 3007, 2930, 1604, 1576, 1511, 1465, 1420, 1309, 1241, 1136, 1057, 992, 849, 781, 751, 726, 695. HRMS [EI-m/z] calcd for C20H19N6O3Cl, [M]+ 426.1207; found, 426.1216.
(1-(4-(Quinazolin-4-ylamino)benzyl)-1H-1,2,3-triazol-4-yl)methanol (5i)
Yield 73% (21 mg); white solid; mp: 268–269 °C; 1H NMR (600 MHz, DMSO-d6): δ 9.84 (s, 1H), 8.58 (s, 1H), 8.54 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.85 (d, J = 8.4 Hz, 3H), 7.79 (d, J = 8.4 Hz, 1H), 7.64 (t, J = 8.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H), 5.56 (s, 2H), 5.16 (t, J = 6 Hz, 1H), 4.51 (d, J = 6.6 Hz, 2 H). 13C NMR (150 MHz, DMSO-d6): δ 158.2, 154.8, 150.1, 148.7, 139.4, 133.5, 131.79, 128.7, 128.2, 126.7, 123.4, 123.1, 123, 115.5, 55.5, 52.8. IR (KBr) [cm–1] ν: 3433, 3308, 3129, 2923, 1604, 1576, 1532, 1426, 1402, 1364, 1325, 1229, 1128, 1049, 93, 770. HRMS [EI-m/z] calcd for C18H16N6O, [M]+ 332.1386; found, 332.13748.
6,7-Dimethoxy-N-(4-((4-(phenoxymethyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)quinazolin-4-amine (5j)
Yield 87% (33 mg); white solid; mp: 224–225 °C; 1H NMR (600 MHz, DMSO-d6): δ 9.52 (s, 1H), 8.44 (s, 1H), 8.29 (s, 1H), 7.83 (s, 1H), 7.79 (d, J = 7.8 Hz, 2H), 7.36 (d, J = 7.8 Hz, 2H), 7.29 (t, J = 7.8 Hz, 2H), 7.18 (s, 1H), 7.02 (d, J = 8.4 Hz, 2H), 6.94 (t, J = 7.2 Hz, 1H), 5.59 (s, 2H), 5.13 (s, 2H), 3.95 (s, 3H), 3.92 (s, 3H). 13C NMR (150 MHz, DMSO-d6): δ 158.4, 156.7, 154.7, 153.2, 149.3, 147.4, 143.5, 139.9, 131.1, 129.9, 128.7, 124.9, 122.8, 121.2, 115.1, 109.3, 107.6, 102.2, 61.4, 56.6, 56.2, 53.0. IR (KBr) [cm–1] ν: 3375, 1621, 1575, 1514, 1461, 1421, 1237, 1137, 997, 853, 758. HRMS [EI-m/z] calcd for C26H24N6O3, [M]+ 468.1910; found, 468.1891.
2-Chloro-6,7-dimethoxy-N-(4-((4-(phenoxymethyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)quinazolin-4-amine (5k)
Yield 84% (29 mg); light yellow solid; mp: 260–261 °C; 1H NMR (600 MHz, DMSO-d6): δ 9.88 (s, 1H), 8.32 (s, 1H), 7.86 (s, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.29 (t, J = 7.2 Hz, 2H), 7.17 (s, 1H), 7.03 (d, J = 7.8 Hz, 1H), 6.95 (t, J = 7.2 Hz, 2H), 5.62 (s, 2H), 5.14 (s, 2H), 3.95 (s, 3H), 3.92 (s, 3H). 13C NMR (150 MHz, DMSO-d6): δ 158.4, 158.3, 155.4, 154.6, 149.4, 148.6, 143.5, 138.8, 132.1, 129.9, 128.8, 125, 123.3, 121.2, 115.1, 107.6, 107.1, 102.6, 61.4, 56.7, 56.4, 52.9. IR (KBr) [cm–1] ν: 3364, 2922, 2853, 1601, 1573, 1515, 1458, 1427, 1293, 1240, 1151, 1004, 961, 840, 758. HRMS (ESI-m/z) calcd for C26H23N6O3Cl, [M + H]+ 503.1598; found, 503.1599.
N-(4-((4-(Phenoxymethyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)quinazolin-4-amine (5l)
Yield 85% (32 mg); white solid; mp: 208–210 °C; 1H NMR (600 MHz, DMSO-d6): δ 9.85 (s, 1H), 8.59 (s, 1H), 8.55 (d, J = 8.4 Hz, 1H), 8.29 (s, 1H), 7.87 (m, J = 6, 3H), 7.79 (d, J = 8.4 Hz, 1H), 7.64 (t, J = 13.2 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.28 (t, J = 7.2 Hz, 2H), 7.03 (d, J = 8.4 Hz, 1H), 6.94 (t, J = 7.8 Hz, 2H), 5.60 (s, 2H), 5.13 (s, 2H). 13C NMR (150 MHz, DMSO-d6): δ 158.4, 158.1, 154.8, 150.1, 143.5, 139.5, 133.52, 131.53, 129.9, 128.8, 128.2, 126.7, 124.9, 123.4, 123, 121.2, 115.5, 115.1, 61.2, 53. IR (KBr) [cm–1] ν: 3355, 3126, 2922, 1606, 1572, 1531, 1498, 1416, 1311, 1218, 1122, 1041, 828, 776, 683, 506. HRMS [EI-m/z] calcd for C24H20N6O, [M]+ 408.1703; found, 408.1703.
(6,7-Dimethoxy-quinazolin-4-yl)-[4-(4-phenylaminomethyl-[1,2,3]triazol-1-ylmethyl)-phenyl]-amine (5m)
Yield 85% (31 mg); light yellow solid; mp: 261–262 °C; 1H NMR (600 MHz, DMSO-d6): δ 9.51 (s, 1H), 8.43 (s, 1H), 8.01 (s, 1H), 7.82 (s, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.18 (s, 1H), 7.06 (t, J = 7.8 Hz, 2H), 6.62 (t, J = 7.8 Hz, 2H), 6.53 (t, J = 12 Hz, 1H), 6.02 (t, J = 6 Hz, 1H), 5.54 (s, 2H), 4.27 (d, J = 6 Hz, 2H), 3.95 (s, 3H), 3.92 (s, 3H). 13C NMR (150 MHz, DMSO-d6): δ 156.7, 154.7, 153.2, 149.3, 148.8, 147.4, 146.5, 139.7, 131.2, 129.2, 128.6, 123.1, 122.8, 116.4, 112.7, 109.3, 107.6, 102.2, 56.6, 56.2, 55.3, 52.8, 39. IR (KBr) [cm–1] ν: 3390, 3282, 3037, 3007, 2930, 1604, 1576, 1511, 1465, 1420, 1309, 1241, 1136, 1057, 992, 849, 781, 751, 726, 695. HRMS (ESI-m/z) calcd for C26H25N7O2, [M + H]+ 468.2148; found, 468.2150.
(2-Chloro-6,7-dimethoxy-quinazolin-4-yl)-[4-(4-phenylaminomethyl-[1,2,3]triazol-1-ylmethyl)-phenyl]-amine (5n)
Yield 82% (29 mg); light yellow solid; mp: 280–281 °C; 1H NMR (600 MHz, DMSO-d6): δ 9.87 (s, 1H), 8.03 (s, 1H), 7.85 (s, 1H), 7.69 (d, J = 6 Hz, 2H), 7.35 (d, J = 9 Hz, 2H), 7.17 (s, 1H), 7.06 (t, J = 8.4 Hz, 2H), 6.62 (d, J = 9.6 Hz, 2H), 6.53 (t, J = 7.2 Hz, 1H), 6.03 (t, J = 6 Hz, 1H), 5.57 (s, 2 H), 4.28 (d, J = 6.6 Hz, 2H), 3.94 (s, 3H), 3.92 (s, 3H). 13C NMR (150 MHz, DMSO-d6): δ 158.3, 155.5, 154.6, 149.4, 148.8, 148.6, 146.5, 138.7, 132.4, 129.2, 128.7, 123.4, 123.2, 116.4, 112.7, 107.6, 107.1, 102.6, 56.7, 56.4, 52.7, 39. IR (KBr) [cm–1] ν: 3406, 1603, 1572, 1513, 1426, 1241, 1150, 961, 844, 755. HRMS (ESI-m/z) calcd for C26H24N7O2Cl, [M + Na]+ 524.1578; found, 524.1586.
[4-(4-Phenylaminomethyl-[1,2,3]triazol-1-ylmethyl)-phenyl]-quinazolin-4-yl-amine (5o)
Yield 81% (29 mg); light yellow solid; mp: 250–251 °C; 1H NMR (600 MHz, DMSO-d6): δ 9.83 (s, 1H), 8.58 (s, 1H), 8.54 (d, J = 8.4 Hz, 1H), 8.01 (s, 1H), 7.86 (m, 3H), 7.79 (d, J = 8.4 Hz, 1H), 7.64 (t, J = 8.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 2H), 7.06 (t, J = 8.4 Hz, 2H), 6.62 (d, J = 7.8 Hz, 2H), 6.53 (t, J = 7.2 Hz, 1H), 6.02 (t, J = 6 Hz, 1H), 5.55 (s, 2H), 4.28 (d, J = 6 Hz, 2H). 13C NMR (150 MHz, DMSO-d6): δ 158.1, 154.8, 150.1, 148.8, 146.5, 139.4, 133.5131.7, 129.2, 128.7, 128.2, 126.7, 123.4, 123.1, 123, 116.4, 115.5, 112.7, 52.8, 39. IR (KBr) [cm–1] ν: 3422, 3289, 2923, 1604, 1571, 1524, 1498, 1414, 1357, 1316, 1256, 1123, 1051, 924, 773, 687, 510. HRMS [EI-m/z] calcd for C24H21N7, [M]+ 407.1858; found, 407.1855.
(2-Chloro-quinazolin-4-yl)-[4-(4-phenyl-[1,2,3]triazol-1-ylmethyl)-phenyl]-amine (5p)
Yield 86% (39 mg); white solid; mp: 204–206 °C; 1H NMR: (600 MHz, DMSO-d6): δ 10.25 (s, 1H), 8.68 (s, 1H), 8.55 (d, J = 8.4 Hz, 1H), 7.86 (m, 3H), 7.79 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 1H), 7.65 (t, J = 7.2 Hz, 1H), 7.43 (m, 4 H), 7.32 (t, J = 7.8 Hz, 1H), 5.65 (s, 2H). 13C NMR (150 MHz, DMSO-d6): δ 159.8, 156.6, 151.3, 147.1, 138.6, 134.6, 132.6, 131.1, 129.4, 128.8, 128.4, 127.4, 127.2, 125.6, 123.9, 123.6, 122, 114.2, 53.1. IR (KBr) [cm–1] ν: 3311, 2922, 2854, 1620, 1564, 1516, 1423, 1342, 1222, 1187, 1077, 1049, 948, 753. HRMS [ESI-m/z] calcd for C23H17N6Cl, [M + H]+ 413.1281; found, 472.1286.
(2-Chloro-quinazolin-4-yl)-{4-[4-(4-ethyl-phenyl)-[1,2,3]triazol-1-ylmethyl]-phenyl}-amine (5q)
Yield 85% (36 mg); white solid; mp: 205–207 °C; 1H NMR (600 MHz, DMSO-d6): δ 10.24 (s, 1H), 8.61 (s, 1H), 8.55 (d, J = 8.4 Hz, 1H), 7.88 (t, J = 8.4 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 7.8 Hz, 1H), 7.66 (t, J = 8.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 7.8 Hz, 2H), 5.64 (s, 2H), 2.61 (q, J = 7.8 Hz, 2H), 1.18 (t, J = 7.8 Hz, 3H). 13C NMR (150 MHz, DMSO-d6): δ 159.8, 156.6, 151.3, 147.2, 143.9, 138.5, 134.7, 132.7, 128.8, 128.7, 128.6, 127.4, 127.1, 125.7, 123.9, 123.6, 121.6, 114.2, 53.1, 28.4, 16. IR (KBr) [cm–1] ν: 3379, 2964, 2924, 1623, 1605, 1562, 1528, 1497, 1424, 1345, 1290, 1220, 1195, 1078, 951, 839, 763. HRMS [ESI-m/z] calcd for C25H21N6Cl, [M + H]+ 441.1594; found, 441.1627.
{1-[4-(2-Chloro-quinazolin-4-ylamino)-benzyl]-1H-[1,2,3]triazol-4-yl}-methanol (5r)
Yield 83% (34 mg); white solid; mp: 224–226 °C; 1H NMR (600 MHz, DMSO-d6): δ 10.24 (s, 1H), 8.54 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.88 (t, J = 7.2 Hz, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 1H) 7.64 (t, J = 7.2 Hz, 1H), 7.38 (d, J = 8.4 Hz, 2H), 5.57 (s, 2H), 5.17 (t, J = 6 Hz, 1H), 4.5 (d, J = 4.8 Hz, 2 H). 13C NMR (150 MHz, DMSO-d6): δ 159.8, 156.6, 151.3, 148.8, 138.5, 134.6, 132.9, 128.8, 127.4, 127.2, 123.9, 123.6, 123.3, 114.2, 55.5, 52.8. IR (KBr) [cm–1] ν: 3334, 2925, 1607, 1566, 1527, 1424, 1410, 1288, 1200, 1126, 1057, 953, 859, 766. HRMS [ESI-m/z] calcd for C28H15N6OCl, [M + H]+ 367.1074; found, 367.1162.
(2-Chloro-quinazolin-4-yl)-[4-(4-phenoxymethyl-[1,2,3]triazol-1-ylmethyl)-phenyl]-amine (5s)
Yield 85% (36 mg); white solid; mp: 200–202 °C; 1H NMR (600 MHz, DMSO-d6): δ 10.25 (s, 1H), 8.56 (d, J = 8.4 Hz, 1H), 8.31 (s, 1H), 7.88 (t, J = 7.2 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 1H), 7.65 (t, J = 8.4 Hz, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.29 (t, J = 8.4 Hz, 2H), 7.02 (d, J = 7.8 Hz, 2H), 6.93 (t, J = 7.2 Hz, 1H), 5.62 (s, 2H), 5.12 (s, 2 H). 13C NMR (150 MHz, DMSO-d6): δ 159.8, 158.5, 156.6, 151.3, 143.5, 138.5, 134.7, 132.7, 129.98, 128.9, 127.4, 127.2, 125.1, 123.9, 123.6, 121.3, 115.1, 114.2, 61.4, 52.9. IR (KBr) [cm–1] ν: 3336, 2922, 2853, 1621, 1565, 1529, 1516, 1426, 1410, 1366, 1237, 1216, 1187, 1058, 1006, 853, 760. HRMS [ESI-m/z] calcd for C24H19N6OCl, [M + H]+ 443.1387; found, 443.1450.
(2-Chloro-quinazolin-4-yl)-[4-(4-phenylaminomethyl-[1,2,3]triazol-1-ylmethyl)-phenyl]-amine (5t)
Yield 85% (36 mg); white solid; mp: 212–214 °C; 1H NMR (300 MHz, DMSO-d6): δ 10.23 (s, 1H), 8.54 (d, J = 8.1 Hz, 1H), 8.03 (s, 1H), 7.89 (t, J = 7.2 Hz, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 1H) 7.64 (t, J = 8.4 Hz, 1H), 7.35 (d, J = 9 Hz, 2H), 7.05 (t, J = 7.2 Hz, 2H), 6.61 (d, J = 7.8 Hz, 2H), 6.52 (t, J = 7.2 Hz, 1H), 6.04 (t, J = 6 Hz, 1H), 5.56 (s, 2H), 4.27 (d, J = 6 Hz, 2H). 13C NMR (150 MHz, DMSO-d6): δ 159.8, 156.6, 151.3, 148.8, 146.5, 138.4, 134.7, 132.9, 129.3, 128.8, 127.4, 127.2, 123.9, 123.6, 123.3, 116.5, 114.2, 112.8, 52.8, 31.2. IR (KBr) [cm–1] ν: 3366, 2922, 2850, 1621, 1604, 1561, 1451, 1409, 1366, 1287, 1195, 1079, 1056, 957, 839, 765. HRMS [ESI-m/z] calcd for C24H20N7Cl, [M + H]+ 442.1547; found, 441.1564.
General Experimental Procedures for Biological Studies
Cytotoxicity Assay
Exponentially growing cells were seeded into 96-well plates at a concentration of 1 × 105 cells per well. After 24 h incubation at 37 °C, the cells were treated with all compounds in different concentrations in triplicates. The cells were incubated for another 24 h. A 20 μL of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide solution (5 mg/mL) was added to all wells and incubated for 4 h at 37 °C. The solution was discarded, and the insoluble dark blue crystals (formazan) were dissolved in 40 μL DMSO. After 15 min, the absorbance was measured using an ELISA reader at a wavelength of 595 nm. The IC50 of all compounds is the concentration (μg/mL) of the compound at which there was 50% growth inhibition with respect to the control culture in different cell lines.
Analysis of Cellular apoptosis
Apoptosis was assayed by using an annexin-V FITC apoptosis detection kit (Calbiochem, CA, USA). Briefly, cells were treated with or without the compounds in a time-dependent manner (0, 12, and 24 h) and then washed and stained with PI and annexin-V-FITC in accordance with the manufacturer’s instructions. The percentages of live, apoptotic, and necrotic cells were determined by the flow cytometric method (Becton Dickinson, San Jose, CA, USA). Data from 1 × 106 cells were analyzed for each sample.
Measurement of ROS
ROS generation was measured by dichlorofluorescein diacetate (DCF-DA). After treatment with the compounds for the time periods (0, 12, and 24 h), the cells were incubated with 10 μM DCF-DA at 37 °C for 20 min. Then cell pellets were suspended in 1 mL phosphate-buffered saline (PBS). Samples were analyzed at an excitation wavelength of 480 nm and an emission wavelength of 525 nm by FACSCalibur flow cytometry (Becton Dickinson, San Jose, CA, USA).
Measurement of Mitochondrial Membrane Potential (JC1 Assay)
MCF-7 cells were seeded for 24 h and then treated with and without compounds in a time-dependent manner (0, 12, and 24 h). Cells were washed twice with ice-cold PBS and then incubated with JC-1 dye (5 μg/mL) in darkness for 20 min at room temperature (37 °C). Emission was determined by the flow cytometric method (Becton Dickinson, San Jose, CA, USA) at 525 nm.
Western Blot
Treated or untreated cells were collected and lysed. Lysates (30 μg of protein per well) were separated by electrophoresis in 12% sodium dodecyl sulfate polyacrylamide gel and electrotransferred to poly(vinylidene difluoride) membranes using a Trans-Blot system (Trans Blot wet transfer; Bio-Rad Laboratories, Inc., Hercules, CA, USA). The membranes were blocked with 5% bovine serum albumin in TBST (tris buffered saline containing 0.1% Tween-20, pH 7.6) for 1 h at room temperature and then incubated with primary antibodies overnight at 4 °C. After washing with TBST, membranes were incubated with horseradish peroxidase conjugated secondary antibody for 1 h. Immunoreactive bands were visualized by chemiluminescence using tetramethylbenzidine as the substrate. β-Actin was used as the loading control.
Supporting Information
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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b01960.
1H NMR and 13C NMR spectra of all compounds and crystal data of compound 5c (PDF)
Crystallographic data of compound 5c (CIF)
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Author Information
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- Biswadip Banerji - Organic & Medicinal Chemistry Division and Academy of Scientific and Innovative Research (AcSIR), , and , Indian Institute of Chemical Biology (CSIR-IICB), 4 Raja S. C. Mullick Road, Kolkata 700032, India;
http://orcid.org/0000-0001-9898-253X;
Acknowledgments
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The authors want to thank CSIR for funding in this project and for a senior research fellowship to K.C. We also thank Dr. Arindam Talukdar, IICB for allowing us to utilize his molecular docking felicities using Discovery studio. The authors also want to thank Mr. Sunil Kumar Killi for his critical comments during the manuscript preparations. Thanks are due to Mr. Sandip Kundu, CSIR-IICB, for recording X-ray data, Mr. E.K. Padmanaban for recording the NMR spectra, Soumik Laha for recording the IR spectra, and Sandip Chowdhury for recording the EI HRMS spectra.
References
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- 4Cohen, M. H.; Williams, G. A.; Sridhara, R.; Chen, G.; Pazdur, R. FDA Drug Approval Summary: Gefitinib (ZD1839) (Iressa(R)) Tablets. Oncologist 2003, 8, 303– 306, DOI: 10.1634/theoncologist.8-4-303Google ScholarThere is no corresponding record for this reference.
- 5Tan, F.; Shi, Y.; Wang, Y.; Ding, L.; Yuan, X.; Sun, Y. Icotinib, a selective EGF receptor tyrosine kinase inhibitor, for the treatment of non-small-cell lung cancer. Future Oncol. 2015, 11, 385– 397, DOI: 10.2217/fon.14.249Google Scholar5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXisF2ls7s%253D&md5=a19fbbc42fd06b8971bc123155d180c0Icotinib, a selective EGF receptor tyrosine kinase inhibitor, for the treatment of non-small-cell lung cancerTan, Fenlai; Shi, Yuankai; Wang, Yinxiang; Ding, Lieming; Yuan, Xiaobin; Sun, YanFuture Oncology (2015), 11 (3), 385-397CODEN: FOUNBN; ISSN:1479-6694. (Future Medicine Ltd.)A review. Advanced non-small-cell lung cancer (NSCLC) is the main cause for cancer-related mortality. Treatments for advanced NSCLC are largely palliative and a benefit plateau appears to have reached with the platinum-based chemotherapy regimens. EGF receptor (EGFR) tyrosine kinase inhibitors gefitinib, erlotinib and afatinib came up with prolonged progression-free survival and improved quality of life, esp. in EGFR-mutated patients. Icotinib is an oral selective EGFR tyrosine kinase, which was approved by China Food and Drug administration in June 2011 for treating advanced NSCLC. Its approval was based on the registered Phase III trial (ICOGEN), which showed icotinib is noninferior to gefitinib. This review will discuss the role of icotinib in NSCLC, and its potential application and ongoing investigations.
- 6Wu, P.; Nielsen, T. E.; Clausen, M. H. FDA-approved small-molecule kinase inhibitors. Trends Pharmacol. Sci. 2015, 36, 422– 439, DOI: 10.1016/j.tips.2015.04.005Google Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXns1KisLg%253D&md5=a6aa3dbb11e6fe3001fa5fa03a4c950aFDA-approved small-molecule kinase inhibitorsWu, Peng; Nielsen, Thomas E.; Clausen, Mads H.Trends in Pharmacological Sciences (2015), 36 (7), 422-439CODEN: TPHSDY; ISSN:0165-6147. (Elsevier Ltd.)A review. Kinases have emerged as one of the most intensively pursued targets in current pharmacol. research, esp. for cancer, due to their crit. roles in cellular signaling. To date, the US FDA has approved 28 small-mol. kinase inhibitors, half of which were approved in the past 3 years. While the clin. data of these approved mols. are widely presented and structure-activity relationship (SAR) has been reported for individual mols., an updated review that analyzes all approved mols. and summarizes current achievements and trends in the field has yet to be found. Here we present all approved small-mol. kinase inhibitors with an emphasis on binding mechanism and structural features, summarize current challenges, and discuss future directions in this field.
- 7Dungo, R. T.; Keating, G. M. Afatinib: first global approval. Drugs 2013, 73, 1503– 1515, DOI: 10.1007/s40265-013-0111-6Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvVWmurnM&md5=21851cbfac56e2fffcba6c731f123cffAfatinib: First Global ApprovalDungo, Rosselle T.; Keating, Gillian M.Drugs (2013), 73 (13), 1503-1515CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)A review. Afatinib, an irreversible inhibitor of the ErbB family of tyrosine kinases, is under development with Boehringer Ingelheim for the once-daily, oral treatment of cancer. Afatinib downregulates ErbB signalling by covalently binding to epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER) 2 and HER4, irreversibly inhibiting tyrosine kinase autophosphorylation. It also inhibits transphosphorylation of HER3. Oral afatinib (Gilotrif®) has been approved in the US for the first-line treatment of patients with metastatic non-small-cell lung cancer (NSCLC) who have tumors with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by a US FDA-approved test. Afatinib has also been approved in Taiwan for the first-line treatment of patients with EGFR mutation-pos. NSCLC. In addn., the European Medicines Agency's Committee for Medicinal Products for Human Use has recommended the approval of afatinib (Giotrif) for the treatment of patients with locally advanced or metastatic NSCLC with activating EGFR mutations who are EGFR tyrosine kinase inhibitor naive. Afatinib is also under regulatory review in Canada, Japan and other Asian countries. This article summarizes the milestones in the development of afatinib, leading to this first approval in patients with metastatic NSCLC.
- 8Leung, E. L.-H.; Fan, X.-X.; Wong, M. P.; Jiang, Z.-H.; Liu, Z.-Q.; Yao, X.-J.; Lu, L.-L.; Zhou, Y.-L.; Yau, L.-F.; Tin, V. P.-C.; Liu, L. Targeting tyrosine kinase inhibitor-resistant non-small cell lung cancer by inducing epidermal growth factor receptor degradation via methionine 790 oxidation. Antioxid. Redox Signaling 2016, 24, 263– 279, DOI: 10.1089/ars.2015.6420Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvV2ktrs%253D&md5=3eefc008e2ebac6a82122f3d87e849c2Targeting Tyrosine Kinase Inhibitor-Resistant Non-Small Cell Lung Cancer by Inducing Epidermal Growth Factor Receptor Degradation via Methionine 790 OxidationLeung, Elaine Lai-Han; Fan, Xing-Xing; Wong, Maria Pik; Jiang, Zhi-Hong; Liu, Zhong-Qiu; Yao, Xiao-Jun; Lu, Lin-Lin; Zhou, Yan-Ling; Yau, Li-Fong; Tin, Vicky Pui-Chi; Liu, LiangAntioxidants & Redox Signaling (2016), 24 (5), 263-279CODEN: ARSIF2; ISSN:1523-0864. (Mary Ann Liebert, Inc.)Aims: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been developed to treat non-small cell lung cancer (NSCLC) patients with EGFR mutation, but TKI resistance is common. Almost half of the acquired resistance patients are due to addnl. T790M mutation on EGFR (EGFRT790M), thus overcoming TKI resistance is important. In this study, we aim to investigate the role of reactive oxygen species (ROS) in TKI resistance as well as the mol. and biol. effects of EGFRT790M after redox manipulation. Results: The basal ROS levels in EGFRT790M-contg. TKI-resistant NSCLC cell lines were substantially high. Sixty-three human lung tumors showed higher NADPH oxidase isoform 2 (NOX2) expression than normal lung tissues, which may contribute to high basal ROS in cancer and poor survival. Interestingly, only NOX3 was upregulated by sanguinarine, a pharmacol. agent to elevate ROS, and resulted in EGFR overoxidn., degrdn., and apoptosis. By contrast, such responses were lacking in EGFRWT cells. Selective EGFRT790M degrdn. was manipulated by redox imbalance between NOX3 and methionine reductase A (MsrA). Furthermore, the in vivo tumor suppression effect of sanguinarine, NOX3 upregulation, and EGFR degrdn. were confirmed. Innovation: We have found a new treatment strategy to overcome TKI resistance by selectively inducing EGFRT790M degrdn. via specific stimulation of methionine 790 (M790) oxidn. It can be achieved via manipulating redox imbalance between NOX3 and MsrA. Conclusion: Targeting EGFR by elevating ROS and redox imbalance is a potential new strategy to develop a new EGFR inhibitor for TKI-resistant patients with a wide therapeutic window between EGFRT790M and EGFRWT. Antioxid. Redox Signal. 24, 263-279.
- 9Schacher-Kaufmann, S.; Pless, M. Acute fatal liver toxicity under erlotinib. Case Rep. Oncol. 2010, 3, 182– 188, DOI: 10.1159/000315366Google Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2sbos1yqsQ%253D%253D&md5=3180e9e98456bd0eacd6dc721c7eb932Acute Fatal Liver Toxicity under ErlotinibSchacher-Kaufmann Sabina; Pless MiklosCase reports in oncology (2010), 3 (2), 182-188 ISSN:1662-6575.We describe the case of a never-smoker who received second-line erlotinib as a treatment for his non-small cell lung cancer. Within one month, acute hepatic failure developed as well as a thrombotic-thrombocytopenic microangiopathy, with fatal outcome. In patients with non-small cell lung cancer, hepatic toxicity of erlotinib is a rare but severe complication; so far three fatal cases have been reported. Patients' liver function should be assessed before starting erlotinib and special care is recommended if pretreatment bilirubin is elevated.
- 10Stathopoulos, G.; Trafalis, D.; Athanasiou, A.; Bardi, G.; Chandrinou, H. Serious hematologic complications following erlotinib treatment. Anticancer Res. 2010, 30, 973– 976Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXlslelu7s%253D&md5=bf3eb9980434cddda198562f4a226716Serious hematologic complications following erlotinib treatmentStathopoulos, G. P.; Trafalis, Dim; Athanasiou, A.; Bardi, G.; Chandrinou, H.Anticancer Research (2010), 30 (3), 973-976CODEN: ANTRD4; ISSN:0250-7005. (International Institute of Anticancer Research)Background: Erlotinib is an oral, small-mol. targeting therapy which inhibits epidermal growth factor tyrosine kinase receptors. Erlotinib has been administered for the treatment of advanced pancreatic cancer and non-small cell lung cancer. Patients and Methods: In the present report, unusual hematol. complications were detected after erlotinib was administered as second-line monotherapy in pretreated patients with advanced non-small cell lung cancer. Four patients pre-treated with cisplatin or its analog-based combinations, were evaluated. Erlotinib was given at a dose of 150 mg daily. In cases of intolerable adverse reactions, the dose was either reduced to 100 mg daily or treatment was interrupted for a max. of two weeks. Results: Serious hematol. toxicity (or complications) developed in these 4 patients after 4-8.5 mo of treatment. Two patients developed leukemias (AML, CML) and two, myelodysplastic syndrome. Conclusion: Whether or not these hematol. complications were related to erlotinib treatment is comprehensively discussed.
- 11Rajput, R.; Mishra, A. P. A review on biological activity of quinazolinones. Int. J. Pharm. Pharm. Sci. 2012, 4, 66– 70Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xms1Cmtrg%253D&md5=253d611f1b2c3e887bf4d403d261026cA review on biological activity of quinazolinonesRajput, Rakhi; Mishra, Abhinav PrasoonInternational Journal of Pharmacy and Pharmaceutical Sciences (2012), 4 (2), 66-70CODEN: IJPPKB; ISSN:0975-1491. (International Journal of Pharmacy and Pharmaceutical Sciences)A review. Quinazolinones is considered as an important chem. synthesis of various physiol. significance and pharmacol. utility. Quinazolinones are a large class of active chem. compds. exhibiting a broad spectrum of biol. activities in animals as well as in humans. Literature studies on quinazolinones have shown that these derivs. possess a wide variety of biol. activities such as anti HIV, anticancer, antifungal, antibacterial, antimutagenic, anticoccidial, anticonvulsant, anti-inflammatory, CNS depressant, antimalarial, antioxidant, antileukemic activity, antileishmanial activity. This review focused on the various biol. activities of quinazolinones.
- 12(a) Cheng, C.-M.; Lee, Y.-J.; Wang, W.-T.; Hsu, C.-T.; Tsai, J.-S.; Wu, C.-M.; Ou, K.-L.; Yang, T.-S. Determining the binding mode and binding affinity constant of tyrosine kinase inhibitor PD153035 to DNA using optical tweezers. Biochem. Biophys. Res. Commun. 2011, 404, 297– 301, DOI: 10.1016/j.bbrc.2010.11.110Google ScholarThere is no corresponding record for this reference.(b) Selvam, T. P.; Kumar, P. V. Quinazoline marketed drugs. Res. Pharm. 2011, 1 ().Google ScholarThere is no corresponding record for this reference.
- 13Medapi, B.; Suryadevara, P.; Renuka, J.; Sridevi, J. P.; Yogeeswari, P.; Sriram, D. 4-Aminoquinoline derivatives as novel Mycobacterium tuberculosis GyrB inhibitors: structural optimization, synthesis and biological evaluation. Eur. J. Med. Chem. 2015, 103, 1– 16, DOI: 10.1016/j.ejmech.2015.06.032Google ScholarThere is no corresponding record for this reference.
- 14Christopher, E.; Bedir, E.; Dunbar, C.; Khan, I. A.; Okunji, C. O.; Schuster, B. M.; Iwu, M. M. Indoloquinazoline Alkaloids fromAraliopsis tabouensis. Helv. Chim. Acta 2003, 86, 2914– 2918, DOI: 10.1002/hlca.200390239Google ScholarThere is no corresponding record for this reference.
- 15Mendoza-Martínez, C.; Galindo-Sevilla, N.; Correa-Basurto, J.; Ugalde-Saldivar, V. M.; Rodríguez-Delgado, R. G.; Hernández-Pineda, J.; Padierna-Mota, C.; Flores-Alamo, M.; Hernández-Luis, F. Antileishmanial activity of quinazoline derivatives: Synthesis, docking screens, molecular dynamic simulations and electrochemical studies. Eur. J. Med. Chem. 2015, 92, 314– 331, DOI: 10.1016/j.ejmech.2014.12.051Google ScholarThere is no corresponding record for this reference.
- 16Antipenko, L. N.; Karpenko, A. V.; Kovalenko, S. I.; Katsev, A. M.; Komarovska-Porokhnyavets, E. Z.; Novikov, V. P. Synthesis, Cytotoxicity by Bioluminescence Inhibition, Antibacterial and Antifungal Activity of ([1,2,4]Triazolo[1,5-c]quinazolin-2-ylthio)carboxylic Acid Amides. Arch. Pharm. 2009, 342, 651– 662, DOI: 10.1002/ardp.200900077Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtlGgsLnM&md5=64f2172cb9615f7a320ad9fb559987cbSynthesis, Cytotoxicity by Bioluminescence Inhibition, Antibacterial and Antifungal Activity of ([1,2,4]Triazolo[1,5-c]quinazolin-2-ylthio)carboxylic Acid AmidesAntipenko, Lyudmila N.; Karpenko, Alexander V.; Kovalenko, Sergey I.; Katsev, Andrew M.; Komarovska-Porokhnyavets, Elena Z.; Novikov, Vladimir P.Archiv der Pharmazie (Weinheim, Germany) (2009), 342 (11), 651-662CODEN: ARPMAS; ISSN:0365-6233. (Wiley-VCH Verlag GmbH & Co. KGaA)We report in this work the synthesis, cytotoxicity, and antimicrobial activity of ([1,2,4]triazolo[1,5-c]quinazolin-2-ylthio)carboxylic acid amides 4-7 in connection with our previous research in the prepn. of triazoloquinazoline derivs. Due to simplicity, general availability of starting materials, and high yields, the most reliable method of synthesis appeared to be the one with N,N-carbonyldiimidazole activation stage. The chem. structures of all obtained substances were deduced from FT-IR, 1H-NMR, EI-MS, and LC-MS spectral data. The results of cytotoxicity evaluated by bioluminescence inhibition of bacterium Photobacterium leiognathi, strain Sh1 showed that compds.4.1, 4.6, and 6.1 were the most cytotoxic. Investigation of the antimicrobial and antifungal activity of amides 4-7 (concn. 5 mg/mL) was carried out by the stiff-plate agar-diffusion method. We found that the compds. possessed low (4.1, 4.7) antifungal activity against Candida tenuis and strong (4.21, 5.1, 5.9) or inefficient (4.7, 4.12, 4.16) activity against Aspergillus niger. Substances 5.1 and 5.9 slightly affected Mycobacterium luteum. Staphylococcus aureus was resistant to all obtained substances, and only the n-butyramide derivs. 7.1 and 7.5 inhibited the growth of Escherichia coli. Hence, there was no strong correlation between bioluminescence inhibition and antimicrobial activity of the investigated substances.
- 17Horne, W. S.; Yadav, M. K.; Stout, C. D.; Ghadiri, M. R. Heterocyclic Peptide Backbone Modifications in an α-Helical Coiled Coil. J. Am. Chem. Soc. 2004, 126, 15366– 15367, DOI: 10.1021/ja0450408Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXptlSgtrw%253D&md5=6f4573960370cdded62c2ca77ad25b04Heterocyclic Peptide Backbone Modifications in an α-Helical Coiled CoilHorne, W. Seth; Yadav, Maneesh K.; Stout, C. David; Ghadiri, M. RezaJournal of the American Chemical Society (2004), 126 (47), 15366-15367CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)In this paper, we present 1,2,3-triazole ε2-amino acids incorporated as a dipeptide surrogate at three positions in the sequence of a known α-helical coiled coil. Biophys. characterization indicates that the modified peptides retain much of the helical structure of the parent sequence, and that the thermodn. stability of the coiled coil depends on the position of the incorporation of the ε-residue. Crystal structures obtained for each peptide give insight into the chem. behavior and conformational preferences of the non-natural amino acid and show that the triazole ring can participate in the backbone hydrogen bonding of the α-helix as well as template an interhelical crossing between chains in the bundle.
- 18(a) Reddy, D. M.; Srinivas, J.; Chashoo, G.; Saxena, A. K.; Sampath Kumar, H. M. 4β-[(4-Alkyl)-1,2,3-triazol-1-yl] podophyllotoxins as anticancer compounds: Design, synthesis and biological evaluation. Eur. J. Med. Chem. 2011, 46, 1983– 1991, DOI: 10.1016/j.ejmech.2011.02.016Google ScholarThere is no corresponding record for this reference.(b) Yoon, J.; Ryu, J.-S. A rapid synthesis of lavendustin-mimetic small molecules by click fragment assembly. Bioorg. Med. Chem. Lett. 2010, 20, 3930– 3935, DOI: 10.1016/j.bmcl.2010.05.014Google Scholar18bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXnsVWis7w%253D&md5=e07a4f2aa1c64bef25822ef2706547bfA rapid synthesis of lavendustin-mimetic small molecules by click fragment assemblyYoon, Jieun; Ryu, Jae-SangBioorganic & Medicinal Chemistry Letters (2010), 20 (13), 3930-3935CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Lavendustin-mimetic small mols. modifying the linker -CH2-NH- with an 1,2,3-triazole ring have been synthesized via a click chem. Two pharmacophoric fragments of lavendustin were varied to investigate chem. space and the auxophoric -CH2-NH- was altered to an 1,2,3-triazole for rapid click conjugation. The small mols. were evaluated against HCT116 colon cancer and CCRF-CEM leukemia cell lines. Among the 28 analogs, 3-phenylpropyl ester I inhibited CCRF-CEM leukemia cell growth with GI50 value of 0.9 μM.
- 19Giffin, M. J.; Heaslet, H.; Brik, A.; Lin, Y.-C.; Cauvi, G.; Wong, C.-H.; McRee, D. E.; Elder, J. H.; Stout, C. D.; Torbett, B. E. A Copper(I)-Catalyzed 1,2,3-Triazole Azide–Alkyne Click Compound Is a Potent Inhibitor of a Multidrug-Resistant HIV-1 Protease Variant. J. Med. Chem. 2008, 51, 6263– 6270, DOI: 10.1021/jm800149mGoogle Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtF2lsrvK&md5=c3ca2b1ae9e3a747ed7161715575f964A Copper(I)-Catalyzed 1,2,3-Triazole Azide-Alkyne Click Compound Is a Potent Inhibitor of a Multidrug-Resistant HIV-1 Protease VariantGiffin, Michael J.; Heaslet, Holly; Brik, Ashraf; Lin, Ying-Chuan; Cauvi, Gabrielle; Wong, Chi-Huey; McRee, Duncan E.; Elder, John H.; Stout, C. David; Torbett, Bruce E.Journal of Medicinal Chemistry (2008), 51 (20), 6263-6270CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Treatment with HIV-1 protease inhibitors, a component of highly active antiretroviral therapy (HAART), often results in viral resistance. Structural and biochem. characterization of a 6X protease mutant arising from in vitro selection with compd. 1, a C2-sym. diol protease inhibitor, has been previously described. We now show that compd. 2, a copper(I)-catalyzed 1,2,3-triazole derived compd. previously shown to be potently effective against wild-type protease (IC50 = 6.0 nM), has low nanomolar activity (IC50 = 15.7 nM) against the multidrug-resistant 6X protease mutant. Compd. 2 displays similar efficacy against wild-type and 6X HIV-1 in viral replication assays. While structural studies of compd. 1 bound to wild-type and mutant proteases revealed a progressive change in binding mode in the mutants, the 1.3 Å resoln. 6X protease-compd. 2 crystal structure reveals nearly identical interactions for 2 as in the wild-type protease complex with very little change in compd. 2 or protease conformation.
- 20Patpi, S. R.; Pulipati, L.; Yogeeswari, P.; Sriram, D.; Jain, N.; Sridhar, B.; Murthy, R.; Anjana Devi, T.; Kalivendi, S. V.; Kantevari, S. Design, Synthesis, and Structure-Activity Correlations of Novel Dibenzo[b,d]furan, Dibenzo[b,d]thiophene, and N-Methylcarbazole Clubbed 1,2,3-Triazoles as Potent Inhibitors of Mycobacterium tuberculosis. J. Med. Chem. 2012, 55, 3911– 3922, DOI: 10.1021/jm300125eGoogle Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XksVymurg%253D&md5=aa0a15ae22de7006b3a367fcaf49576bDesign, Synthesis, and Structure-Activity Correlations of Novel Dibenzo[b,d]furan, Dibenzo[b,d]thiophene, and N-Methylcarbazole Clubbed 1,2,3-Triazoles as Potent Inhibitors of Mycobacterium tuberculosisPatpi, Santhosh Reddy; Pulipati, Lokesh; Yogeeswari, Perumal; Sriram, Dharmarajan; Jain, Nishant; Sridhar, Balasubramanian; Murthy, Ramalinga; T, Anjana Devi; Kalivendi, Shasi Vardhan; Kantevari, SrinivasJournal of Medicinal Chemistry (2012), 55 (8), 3911-3922CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A mol. hybridization approach is an emerging structural modification tool to design new mols. with improved pharmacophoric properties. In this study, 1,2,3-triazole-based Mycobacterium tuberculosis inhibitors and synthetic and natural product-based tricyclic (carbazole, dibenzo[b,d]furan, and dibenzo[b,d]thiophene) antimycobacterial agents were integrated in one mol. platform to prep. various novel clubbed 1,2,3-triazole hybrids using click chem. Structure-activity correlations and in vitro activity against M. tuberculosis strain H37Rv of new analogs revealed the order: dibenzo[b,d]thiophene > dibenzo[b,d]furan > 9-methyl-9H-carbazole series. Some of the most potent M. tuberculosis inhibitors with MIC = 0.78 μg/mL (∼1.9 μM) displayed a low cytotoxicity and high selectivity index (50-255) against four different human cancer cell lines. These results together provided the potential importance of mol. hybridization and the development of triazole clubbed dibenzo[b,d]thiophene-based lead candidates to treat mycobacterial infections.
- 21De Simone, R.; Chini, M. G.; Bruno, I.; Riccio, R.; Mueller, D.; Werz, O.; Bifulco, G. Structure-Based Discovery of Inhibitors of Microsomal Prostaglandin E2Synthase–1, 5-Lipoxygenase and 5-Lipoxygenase-Activating Protein: Promising Hits for the Development of New Anti-inflammatory Agents. J. Med. Chem. 2011, 54, 1565– 1575, DOI: 10.1021/jm101238dGoogle Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXitVKqtbw%253D&md5=7e4379cce59ecf39290522c8238a3647Structure-Based Discovery of Inhibitors of Microsomal Prostaglandin E2 Synthase-1, 5-Lipoxygenase and 5-Lipoxygenase-Activating Protein: Promising Hits for the Development of New Anti-inflammatory AgentsDe Simone, Rosa; Chini, Maria Giovanna; Bruno, Ines; Riccio, Raffaele; Mueller, Daniela; Werz, Oliver; Bifulco, GiuseppeJournal of Medicinal Chemistry (2011), 54 (6), 1565-1575CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Microsomal prostaglandin E2 synthase (mPGES)-1 catalyzes the transformation of PGH2 to PGE2 that is involved in several pathologies like fever, pain, and inflammatory disorders. To identify novel mPGES-1 inhibitors, we used in silico screening to rapidly direct the synthesis, based on the copper-catalyzed 3 + 2 Huisgen's reaction (click chem.), of potential inhibitors. We designed 26 new triazole-based compds. in accordance with the pocket binding requirements of human mPGES-1. Docking results, in agreement with ligand efficiency values, suggested the synthesis of 15 compds. that at least in theory were shown to be more efficient in inhibiting mPGES-1. Biol. evaluation of these selected compds. has disclosed three new potential anti-inflammatory drugs: (I) compd. 4 displaying selectivity for mPGES-1 with an IC50 value of 3.2 μM, (II) compd. 20 that dually inhibits 5-lipoxygenase and mPGES-1, and (III) compd. 7 apparently acting as 5-lipoxygenase-activating protein inhibitor (IC50 = 0.4 μM).
- 22Banerji, B.; Killi, S. K.; Katarkar, A.; Chatterjee, S.; Tangella, Y.; Prodhan, C.; Chaudhuri, K. Neo-tanshinlactone D-ring modified novel analogues induce apoptosis in human breast cancer cell via DNA damage. Bioorg. Med. Chem. 2017, 25, 202– 212, DOI: 10.1016/j.bmc.2016.10.026Google ScholarThere is no corresponding record for this reference.
- 23Viegas-Junior, C.; Barreiro, E. J.; Fraga, C. A. M. Molecular hybridization: a useful tool in the design of new drug prototypes. Bioorg. Med. Chem. 2007, 14, 1829– 1852, DOI: 10.2174/092986707781058805Google ScholarThere is no corresponding record for this reference.
- 24Stamos, J.; Sliwkowski, M. X.; Eigenbrot, C. Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J. Biol. Chem. 2002, 277, 46265– 46272, DOI: 10.1074/jbc.m207135200Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XovFKhsL4%253D&md5=c63c60b93756bd45fb2375c56ba38941Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitorStamos, Jennifer; Sliwkowski, Mark X.; Eigenbrot, CharlesJournal of Biological Chemistry (2002), 277 (48), 46265-46272CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)The crystal structure of the kinase domain from the epidermal growth factor receptor (EGFRK) including forty amino acids from the carboxyl-terminal tail has been detd. to 2.6-Å resoln., both with and without an EGFRK-specific inhibitor currently in Phase III clin. trials as an anti-cancer agent, erlotinib (OSI-774, CP-358,774, Tarceva). The EGFR family members are distinguished from all other known receptor tyrosine kinases in possessing constitutive kinase activity without a phosphorylation event within their kinase domains. Despite its lack of phosphorylation, we find that the EGFRK activation loop adopts a conformation similar to that of the phosphorylated active form of the kinase domain from the insulin receptor. Surprisingly, key residues of a putative dimerization motif lying between the EGFRK domain and carboxyl-terminal substrate docking sites are found in close contact with the kinase domain. Significant intermol. contacts involving the carboxyl-terminal tail are discussed with respect to receptor oligomerization.
- 25Towbin, H.; Staehelin, T.; Gordon, J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc. Natl. Acad. Sci. U. S. A. 1979, 76, 4350– 4354, DOI: 10.1073/pnas.76.9.4350Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1MXmtVKltLw%253D&md5=39eea3d100df7959e5d12e39e14cecbfElectrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: Procedure and some applicationsTowbin, Harry; Staehelin, Theophil; Gordon, JulianProceedings of the National Academy of Sciences of the United States of America (1979), 76 (9), 4350-4CODEN: PNASA6; ISSN:0027-8424.A method was devised for the electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets. The method results in quant. transfer of ribosomal proteins from gels contg. urea. For Na dodecyl sulfate gels, the original band pattern was obtained with no loss of resoln., but the transfer was not quant. The method allows detection of proteins by autoradiog. and is simpler than conventional procedures. The immobilized proteins were detectable by immunol. procedures. All addnl. binding capacity on the nitrocellulose was blocked with excess protein; then, a specific antibody was bound and, finally, a 2nd antibody directed against the 1st antibody. The 2nd antibody was wither radioactively labeled or conjugated to fluorescein or to peroxidase. The specific protein was then detected by either autoradiog., under UV light, or by the peroxidase reaction product, resp. In the latter case, as little as 100 pg of protein was clearly detectable.
- 26Lambert, A. J.; Brand, M. D. Superoxide production by NADH:ubiquinone oxidoreductase (complex I) depends on the pH gradient across the mitochondrial inner membrane. Biochem. J. 2004, 382, 511– 517, DOI: 10.1042/bj20040485Google ScholarThere is no corresponding record for this reference.
- 27Dey, S. K.; Bose, D.; Hazra, A.; Naskar, S.; Nandy, A.; Munda, R. N.; Das, S.; Chatterjee, N.; Mondal, N. B.; Banerjee, S.; Saha, K. D. Cytotoxic activity and apoptosis-inducing potential of di-spiropyrrolidino and di-spiropyrrolizidino oxindole andrographolide derivatives. PLoS One 2013, 8, e58055, DOI: 10.1371/journal.pone.0058055Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXktlSrsLg%253D&md5=64ae726bf948e1fc8225ad1a9ae8f516Cytotoxic activity and apoptosis-inducing potential of di-spiropyrrolidino and di-spiropyrrolizidino oxindole andrographolide derivativesDey, Sumit Kumar; Bose, Dipayan; Hazra, Abhijit; Naskar, Subhendu; Nandy, Abhishek; Munda, Rudra Narayan; Das, Subhadip; Chatterjee, Nabanita; Mondal, Nirup Bikash; Banerjee, Sukdeb; Das Saha, KrishnaPLoS One (2013), 8 (3), e58055CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Anticancer role of andrographolide is well documented. To find novel potent derivs. with improved cytotoxicity than andrographolide on cancer cells, two series of di-spiropyrrolidino- and di-spiropyrrolizidino oxindole andrographolide derivs. prepd. by cyclo-addn. of azomethine ylide along with sarcosine or proline (viz. sarcosine and proline series resp.) and substitution of different functional groups (-CH3, -OCH3 and halogens) were examd. for their cytotoxic effect on a panel of six human cancer cell lines (colorectal carcinoma HCT116 cells, pancreatic carcinoma MiaPaCa-2 cells, hepatocarcinoma HepG2 cells, cervical carcinoma HeLa cells, lung carcinoma A549 and melanoma A375 cells). Except halogen substituted derivs. of proline series (viz. CY2, CY14 and CY15 for Br, Cl and I substitution resp.), none of the other derivs. showed improved cytotoxicity than andrographolide in the cancer cell lines examd. Order of cytotoxicity of the potent compds. is CY2>CY14>CY15>andrographolide. Higher toxicity was obsd. in HCT116, MiaPaCa-2 and HepG2 cells. CY2, induced death of HCT116 (GI50 10.5), MiaPaCa-2 (GI50 11.2) and HepG2 (GI50 16.6) cells were assocd. with cell rounding, nuclear fragmentation and increased percentage of apoptotic cells, cell cycle arrest at G1 phase, ROS generation and involvement of mitochondrial pathway. Upregulation of Bax, Bad, p53, caspases-3,-9 and cleaved PARP; downregulation of Bcl-2, cytosolic NF-κB p65, PI3K and p-Akt; translocation of P53/P21, NF-κB p65 were seen in CY2 treated HCT116 cells. Thus, three halogenated di-spiropyrrolizidino oxindole derivs. of andrographolide are found to be more cytotoxic than andrographolide in some cancer cells. The most potent deriv., CY2 induced death of the cancer cells involves ROS dependent mitochondrial pathway like andrographolide.
- 28Nandy, A.; Dey, S.; Das, S.; Munda, R.; Dinda, J.; Saha, K. Gold (I) N-heterocyclic carbene complex inhibits mouse melanoma growth by p53 upregulation. Mol. Cancer 2014, 13, 57, DOI: 10.1186/1476-4598-13-57Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXivFWhtbc%253D&md5=40df17b4bddf6dce687596250172e457Gold (I) N-heterocyclic carbene complex inhibits mouse melanoma growth by p53 upregulationNandy, Abhishek; Dey, Sumit Kumar; Das, Sujata; Munda, Rudra Narayan; Dinda, Joydev; Das Saha, KrishnaMolecular Cancer (2014), 13 (), 57/1-57/14, 14 pp.CODEN: MCOACG; ISSN:1476-4598. (BioMed Central Ltd.)Background: Cancer treatment using gold (I) complexes is becoming popular. In this study, a gold (I) N-heterocyclic complex designated as complex 3 was synthesized, its cytotoxicity was examd., and its anti-melanoma activity was evaluated in vitro and in vivo. Methods: Viability of cancer cells was detd. by MTT assay upon treatment with various concns. of a gold (I) N-heterocyclic carbene complex (complex 3) in a dose and time dependent manner. Mouse melanoma cells B16F10 were selected for further apoptotic studies, including flowcytometric anal. of annexin binding, cell cycle arrest, intracellular ROS generation and loss in the mitochondrial membrane potential. ELISA based assays were done for caspase activities and western blots for detg. the expression of various survival and apoptotic proteins. Immunocytol. was performed to visualize the translocation of p53 to the nucleus. B16F10 cells were inoculated into mice and post tumor formation, complex 3 was administered. Immunohistol. was performed to det. the expressions of p53, p21, NF-κB (p65 and p50), MMP-9 and VEGF. Student's t test was used for detg. statistical significance. The survival rate data were analyzed by Kaplan-Meier plots. Results: Complex 3 markedly inhibited the growth of HCT 116, HepG2, and A549, and induced apoptosis in B16F10 cells with nuclear condensation, DNA fragmentation, externalization of phosphatidylserine, activation of caspase 3 and caspase 9, PARP cleavage, downregulation of Bcl-2, upregulation of Bax, cytosolic cytochrome c elevation, ROS generation, and mitochondrial membrane potential loss indicating the involvement of an intrinsic mitochondrial death pathway. Further, upregulation of p53, p-p53 (ser 15) and p21 indicated the role of p53 in complex 3 mediated apoptosis. The complex reduced tumor size, and caused upregulation of p53 and p21 along with downregulation of NF-κB (p65 and p50), VEGF and MMP-9. These results suggest that it induced anti-melanoma effect in vitro and in vivo by modulating p53 and other apoptotic factors. Conclusions: The gold (I) N-heterocyclic carbene complex (C22H26N6AuO2PF6) designated as complex 3 induced ROS and p53 dependent apoptosis in B16F10 cells involving the mitochondrial death pathway along with suppression of melanoma tumor growth by regulating the levels of pro and anti apoptotic factors (p53, p21, NF-κB, VEGF and MMP-9).
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- Fanyong Yan, Hao Zhang, Xing Li, Xiaodong Sun, Yingxia Jiang, Yali Cui. A fluorescein-coumarin based ratiometric fluorescent probe for detecting hydrazine and its real applications in cells imaging. Talanta 2021, 223 , 121779. https://doi.org/10.1016/j.talanta.2020.121779
- Luiz Claudio Ferreira Pimentel, Lucas Villas Boas Hoelz, Henayle Fernandes Canzian, Frederico Silva Castelo Branco, Andressa Paula de Oliveira, Vinicius Rangel Campos, Floriano Paes Silva Júnior, Rafael Ferreira Dantas, Jackson Antônio Lamounier Camargos Resende, Anna Claudia Cunha, Nubia Boechat, Mônica Macedo Bastos. (Phenylamino)pyrimidine-1,2,3-triazole derivatives as analogs of imatinib: searching for novel compounds against chronic myeloid leukemia. Beilstein Journal of Organic Chemistry 2021, 17 , 2260-2269. https://doi.org/10.3762/bjoc.17.144
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Abstract
Figure 1
Figure 1. Chemical structure of some reported anticancer agents.
Figure 2
Figure 2. Design strategy of the target molecule.
Scheme 1
Scheme 1. Synthetic Route of the Target Molecule and Crystal Structure of Compound 5c (ccdc: 1854806)aaReagents and conditions: (a) NaN3, THF/H2O (4:1), RT, 1 h, 95%; (b) CuI, THF, different alkynes, reflux, 80 °C, 3 h, 80–85%; (c) Fe, NH4Cl, EtOH/H2O (1:1), reflux, 80 °C, 2 h, 76–80%; (d) NaOAc, THF/H2O (4:1), different quinazolines, reflux, 80 °C, 6 h, 73–88%.
Figure 3
Figure 3. (a) Surface representation of the EGFR protein (PDB ID 1M17) along with compound 5b (magenta) and erlotinib (blue). (b,c) Three-dimensional (3D) and two-dimensional (2D) representation of molecular docking interactions of compound 5b in the ATP-binding pocket of EGFR tyrosine kinase (1M17). (d,e) 3D and 2D molecular docking interactions of erlotinib in the ATP-binding pocket of EGFR tyrosine kinase.
Figure 4
Figure 4. Western blot image of expression of EGFR and p-EGFR upon treatment with compound 5b and erlotinib (positive control).
Figure 5
Figure 5. Effect of compound 5b in (i) apoptosis induction through ROS generation, (ii) analysis of apoptosis, and (iii) apoptosis induction through the mitochondrial membrane potential assay in MCF-7 cells at different time points (0–24) h.
References
This article references 28 other publications.
- 1Fidler, M. M.; Bray, F.; Soerjomataram, I. The global cancer burden and human development: A review. Scand. J. Public Health 2018, 46, 27– 36, DOI: 10.1177/14034948177154001https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cjjslentg%253D%253D&md5=94ce8f48e941130e946974bb5d60e747The global cancer burden and human development: A reviewFidler Miranda M; Bray Freddie; Soerjomataram IsabelleScandinavian journal of public health (2018), 46 (1), 27-36 ISSN:.AIMS: This review examines the links between human development and cancer overall and for specific types of cancer, as well as cancer-related risk-factors and outcomes, such as disability and life expectancy. METHODS: To assess human development, the Human Development Index was utilized continuously and according to four levels (low, medium, high, very high), where the low and very high categories include the least and most developed countries, respectively. All studies that assessed aspects of the global cancer burden using this measure were reviewed. RESULTS: Although the present cancer incidence burden is greater in higher Human Development Index countries, a greater proportion of the global mortality burden is observed in less developed countries, with a higher mean fatality rate in the latter countries. Further, the future cancer burden is expected to disproportionally affect less developed regions; in particular, it has been estimated that low and medium Human Development Index countries will experience a 100% and 81% increase in cancer incidence from 2008 to 2030, respectively. Disparities were also observed in risk factors and average health outcomes, such as a greater number of years of life lost prematurely and fewer cancer-related gains in life expectancy observed in lower versus higher Human Development Index settings. CONCLUSIONS: From a global perspective, there remain clear disparities in the cancer burden according to national Human Development Index scores. International efforts are needed to aid countries in social and economic transition in order to efficiently plan, implement and evaluate cancer control initiatives as a means to reduce the widening gap in cancer occurrence and survival worldwide.
- 2Ciardiello, F.; Tortora, G. Epidermal growth factor receptor (EGFR) as a target in cancer therapy: understanding the role of receptor expression and other molecular determinants that could influence the response to anti-EGFR drugs. Eur. J. Cancer 2003, 39, 1348– 1354, DOI: 10.1016/s0959-8049(03)00235-1There is no corresponding record for this reference.
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- 4Cohen, M. H.; Williams, G. A.; Sridhara, R.; Chen, G.; Pazdur, R. FDA Drug Approval Summary: Gefitinib (ZD1839) (Iressa(R)) Tablets. Oncologist 2003, 8, 303– 306, DOI: 10.1634/theoncologist.8-4-303There is no corresponding record for this reference.
- 5Tan, F.; Shi, Y.; Wang, Y.; Ding, L.; Yuan, X.; Sun, Y. Icotinib, a selective EGF receptor tyrosine kinase inhibitor, for the treatment of non-small-cell lung cancer. Future Oncol. 2015, 11, 385– 397, DOI: 10.2217/fon.14.2495https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXisF2ls7s%253D&md5=a19fbbc42fd06b8971bc123155d180c0Icotinib, a selective EGF receptor tyrosine kinase inhibitor, for the treatment of non-small-cell lung cancerTan, Fenlai; Shi, Yuankai; Wang, Yinxiang; Ding, Lieming; Yuan, Xiaobin; Sun, YanFuture Oncology (2015), 11 (3), 385-397CODEN: FOUNBN; ISSN:1479-6694. (Future Medicine Ltd.)A review. Advanced non-small-cell lung cancer (NSCLC) is the main cause for cancer-related mortality. Treatments for advanced NSCLC are largely palliative and a benefit plateau appears to have reached with the platinum-based chemotherapy regimens. EGF receptor (EGFR) tyrosine kinase inhibitors gefitinib, erlotinib and afatinib came up with prolonged progression-free survival and improved quality of life, esp. in EGFR-mutated patients. Icotinib is an oral selective EGFR tyrosine kinase, which was approved by China Food and Drug administration in June 2011 for treating advanced NSCLC. Its approval was based on the registered Phase III trial (ICOGEN), which showed icotinib is noninferior to gefitinib. This review will discuss the role of icotinib in NSCLC, and its potential application and ongoing investigations.
- 6Wu, P.; Nielsen, T. E.; Clausen, M. H. FDA-approved small-molecule kinase inhibitors. Trends Pharmacol. Sci. 2015, 36, 422– 439, DOI: 10.1016/j.tips.2015.04.0056https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXns1KisLg%253D&md5=a6aa3dbb11e6fe3001fa5fa03a4c950aFDA-approved small-molecule kinase inhibitorsWu, Peng; Nielsen, Thomas E.; Clausen, Mads H.Trends in Pharmacological Sciences (2015), 36 (7), 422-439CODEN: TPHSDY; ISSN:0165-6147. (Elsevier Ltd.)A review. Kinases have emerged as one of the most intensively pursued targets in current pharmacol. research, esp. for cancer, due to their crit. roles in cellular signaling. To date, the US FDA has approved 28 small-mol. kinase inhibitors, half of which were approved in the past 3 years. While the clin. data of these approved mols. are widely presented and structure-activity relationship (SAR) has been reported for individual mols., an updated review that analyzes all approved mols. and summarizes current achievements and trends in the field has yet to be found. Here we present all approved small-mol. kinase inhibitors with an emphasis on binding mechanism and structural features, summarize current challenges, and discuss future directions in this field.
- 7Dungo, R. T.; Keating, G. M. Afatinib: first global approval. Drugs 2013, 73, 1503– 1515, DOI: 10.1007/s40265-013-0111-67https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvVWmurnM&md5=21851cbfac56e2fffcba6c731f123cffAfatinib: First Global ApprovalDungo, Rosselle T.; Keating, Gillian M.Drugs (2013), 73 (13), 1503-1515CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)A review. Afatinib, an irreversible inhibitor of the ErbB family of tyrosine kinases, is under development with Boehringer Ingelheim for the once-daily, oral treatment of cancer. Afatinib downregulates ErbB signalling by covalently binding to epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER) 2 and HER4, irreversibly inhibiting tyrosine kinase autophosphorylation. It also inhibits transphosphorylation of HER3. Oral afatinib (Gilotrif®) has been approved in the US for the first-line treatment of patients with metastatic non-small-cell lung cancer (NSCLC) who have tumors with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by a US FDA-approved test. Afatinib has also been approved in Taiwan for the first-line treatment of patients with EGFR mutation-pos. NSCLC. In addn., the European Medicines Agency's Committee for Medicinal Products for Human Use has recommended the approval of afatinib (Giotrif) for the treatment of patients with locally advanced or metastatic NSCLC with activating EGFR mutations who are EGFR tyrosine kinase inhibitor naive. Afatinib is also under regulatory review in Canada, Japan and other Asian countries. This article summarizes the milestones in the development of afatinib, leading to this first approval in patients with metastatic NSCLC.
- 8Leung, E. L.-H.; Fan, X.-X.; Wong, M. P.; Jiang, Z.-H.; Liu, Z.-Q.; Yao, X.-J.; Lu, L.-L.; Zhou, Y.-L.; Yau, L.-F.; Tin, V. P.-C.; Liu, L. Targeting tyrosine kinase inhibitor-resistant non-small cell lung cancer by inducing epidermal growth factor receptor degradation via methionine 790 oxidation. Antioxid. Redox Signaling 2016, 24, 263– 279, DOI: 10.1089/ars.2015.64208https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvV2ktrs%253D&md5=3eefc008e2ebac6a82122f3d87e849c2Targeting Tyrosine Kinase Inhibitor-Resistant Non-Small Cell Lung Cancer by Inducing Epidermal Growth Factor Receptor Degradation via Methionine 790 OxidationLeung, Elaine Lai-Han; Fan, Xing-Xing; Wong, Maria Pik; Jiang, Zhi-Hong; Liu, Zhong-Qiu; Yao, Xiao-Jun; Lu, Lin-Lin; Zhou, Yan-Ling; Yau, Li-Fong; Tin, Vicky Pui-Chi; Liu, LiangAntioxidants & Redox Signaling (2016), 24 (5), 263-279CODEN: ARSIF2; ISSN:1523-0864. (Mary Ann Liebert, Inc.)Aims: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been developed to treat non-small cell lung cancer (NSCLC) patients with EGFR mutation, but TKI resistance is common. Almost half of the acquired resistance patients are due to addnl. T790M mutation on EGFR (EGFRT790M), thus overcoming TKI resistance is important. In this study, we aim to investigate the role of reactive oxygen species (ROS) in TKI resistance as well as the mol. and biol. effects of EGFRT790M after redox manipulation. Results: The basal ROS levels in EGFRT790M-contg. TKI-resistant NSCLC cell lines were substantially high. Sixty-three human lung tumors showed higher NADPH oxidase isoform 2 (NOX2) expression than normal lung tissues, which may contribute to high basal ROS in cancer and poor survival. Interestingly, only NOX3 was upregulated by sanguinarine, a pharmacol. agent to elevate ROS, and resulted in EGFR overoxidn., degrdn., and apoptosis. By contrast, such responses were lacking in EGFRWT cells. Selective EGFRT790M degrdn. was manipulated by redox imbalance between NOX3 and methionine reductase A (MsrA). Furthermore, the in vivo tumor suppression effect of sanguinarine, NOX3 upregulation, and EGFR degrdn. were confirmed. Innovation: We have found a new treatment strategy to overcome TKI resistance by selectively inducing EGFRT790M degrdn. via specific stimulation of methionine 790 (M790) oxidn. It can be achieved via manipulating redox imbalance between NOX3 and MsrA. Conclusion: Targeting EGFR by elevating ROS and redox imbalance is a potential new strategy to develop a new EGFR inhibitor for TKI-resistant patients with a wide therapeutic window between EGFRT790M and EGFRWT. Antioxid. Redox Signal. 24, 263-279.
- 9Schacher-Kaufmann, S.; Pless, M. Acute fatal liver toxicity under erlotinib. Case Rep. Oncol. 2010, 3, 182– 188, DOI: 10.1159/0003153669https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2sbos1yqsQ%253D%253D&md5=3180e9e98456bd0eacd6dc721c7eb932Acute Fatal Liver Toxicity under ErlotinibSchacher-Kaufmann Sabina; Pless MiklosCase reports in oncology (2010), 3 (2), 182-188 ISSN:1662-6575.We describe the case of a never-smoker who received second-line erlotinib as a treatment for his non-small cell lung cancer. Within one month, acute hepatic failure developed as well as a thrombotic-thrombocytopenic microangiopathy, with fatal outcome. In patients with non-small cell lung cancer, hepatic toxicity of erlotinib is a rare but severe complication; so far three fatal cases have been reported. Patients' liver function should be assessed before starting erlotinib and special care is recommended if pretreatment bilirubin is elevated.
- 10Stathopoulos, G.; Trafalis, D.; Athanasiou, A.; Bardi, G.; Chandrinou, H. Serious hematologic complications following erlotinib treatment. Anticancer Res. 2010, 30, 973– 97610https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXlslelu7s%253D&md5=bf3eb9980434cddda198562f4a226716Serious hematologic complications following erlotinib treatmentStathopoulos, G. P.; Trafalis, Dim; Athanasiou, A.; Bardi, G.; Chandrinou, H.Anticancer Research (2010), 30 (3), 973-976CODEN: ANTRD4; ISSN:0250-7005. (International Institute of Anticancer Research)Background: Erlotinib is an oral, small-mol. targeting therapy which inhibits epidermal growth factor tyrosine kinase receptors. Erlotinib has been administered for the treatment of advanced pancreatic cancer and non-small cell lung cancer. Patients and Methods: In the present report, unusual hematol. complications were detected after erlotinib was administered as second-line monotherapy in pretreated patients with advanced non-small cell lung cancer. Four patients pre-treated with cisplatin or its analog-based combinations, were evaluated. Erlotinib was given at a dose of 150 mg daily. In cases of intolerable adverse reactions, the dose was either reduced to 100 mg daily or treatment was interrupted for a max. of two weeks. Results: Serious hematol. toxicity (or complications) developed in these 4 patients after 4-8.5 mo of treatment. Two patients developed leukemias (AML, CML) and two, myelodysplastic syndrome. Conclusion: Whether or not these hematol. complications were related to erlotinib treatment is comprehensively discussed.
- 11Rajput, R.; Mishra, A. P. A review on biological activity of quinazolinones. Int. J. Pharm. Pharm. Sci. 2012, 4, 66– 7011https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xms1Cmtrg%253D&md5=253d611f1b2c3e887bf4d403d261026cA review on biological activity of quinazolinonesRajput, Rakhi; Mishra, Abhinav PrasoonInternational Journal of Pharmacy and Pharmaceutical Sciences (2012), 4 (2), 66-70CODEN: IJPPKB; ISSN:0975-1491. (International Journal of Pharmacy and Pharmaceutical Sciences)A review. Quinazolinones is considered as an important chem. synthesis of various physiol. significance and pharmacol. utility. Quinazolinones are a large class of active chem. compds. exhibiting a broad spectrum of biol. activities in animals as well as in humans. Literature studies on quinazolinones have shown that these derivs. possess a wide variety of biol. activities such as anti HIV, anticancer, antifungal, antibacterial, antimutagenic, anticoccidial, anticonvulsant, anti-inflammatory, CNS depressant, antimalarial, antioxidant, antileukemic activity, antileishmanial activity. This review focused on the various biol. activities of quinazolinones.
- 12(a) Cheng, C.-M.; Lee, Y.-J.; Wang, W.-T.; Hsu, C.-T.; Tsai, J.-S.; Wu, C.-M.; Ou, K.-L.; Yang, T.-S. Determining the binding mode and binding affinity constant of tyrosine kinase inhibitor PD153035 to DNA using optical tweezers. Biochem. Biophys. Res. Commun. 2011, 404, 297– 301, DOI: 10.1016/j.bbrc.2010.11.110There is no corresponding record for this reference.(b) Selvam, T. P.; Kumar, P. V. Quinazoline marketed drugs. Res. Pharm. 2011, 1 ().There is no corresponding record for this reference.
- 13Medapi, B.; Suryadevara, P.; Renuka, J.; Sridevi, J. P.; Yogeeswari, P.; Sriram, D. 4-Aminoquinoline derivatives as novel Mycobacterium tuberculosis GyrB inhibitors: structural optimization, synthesis and biological evaluation. Eur. J. Med. Chem. 2015, 103, 1– 16, DOI: 10.1016/j.ejmech.2015.06.032There is no corresponding record for this reference.
- 14Christopher, E.; Bedir, E.; Dunbar, C.; Khan, I. A.; Okunji, C. O.; Schuster, B. M.; Iwu, M. M. Indoloquinazoline Alkaloids fromAraliopsis tabouensis. Helv. Chim. Acta 2003, 86, 2914– 2918, DOI: 10.1002/hlca.200390239There is no corresponding record for this reference.
- 15Mendoza-Martínez, C.; Galindo-Sevilla, N.; Correa-Basurto, J.; Ugalde-Saldivar, V. M.; Rodríguez-Delgado, R. G.; Hernández-Pineda, J.; Padierna-Mota, C.; Flores-Alamo, M.; Hernández-Luis, F. Antileishmanial activity of quinazoline derivatives: Synthesis, docking screens, molecular dynamic simulations and electrochemical studies. Eur. J. Med. Chem. 2015, 92, 314– 331, DOI: 10.1016/j.ejmech.2014.12.051There is no corresponding record for this reference.
- 16Antipenko, L. N.; Karpenko, A. V.; Kovalenko, S. I.; Katsev, A. M.; Komarovska-Porokhnyavets, E. Z.; Novikov, V. P. Synthesis, Cytotoxicity by Bioluminescence Inhibition, Antibacterial and Antifungal Activity of ([1,2,4]Triazolo[1,5-c]quinazolin-2-ylthio)carboxylic Acid Amides. Arch. Pharm. 2009, 342, 651– 662, DOI: 10.1002/ardp.20090007716https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtlGgsLnM&md5=64f2172cb9615f7a320ad9fb559987cbSynthesis, Cytotoxicity by Bioluminescence Inhibition, Antibacterial and Antifungal Activity of ([1,2,4]Triazolo[1,5-c]quinazolin-2-ylthio)carboxylic Acid AmidesAntipenko, Lyudmila N.; Karpenko, Alexander V.; Kovalenko, Sergey I.; Katsev, Andrew M.; Komarovska-Porokhnyavets, Elena Z.; Novikov, Vladimir P.Archiv der Pharmazie (Weinheim, Germany) (2009), 342 (11), 651-662CODEN: ARPMAS; ISSN:0365-6233. (Wiley-VCH Verlag GmbH & Co. KGaA)We report in this work the synthesis, cytotoxicity, and antimicrobial activity of ([1,2,4]triazolo[1,5-c]quinazolin-2-ylthio)carboxylic acid amides 4-7 in connection with our previous research in the prepn. of triazoloquinazoline derivs. Due to simplicity, general availability of starting materials, and high yields, the most reliable method of synthesis appeared to be the one with N,N-carbonyldiimidazole activation stage. The chem. structures of all obtained substances were deduced from FT-IR, 1H-NMR, EI-MS, and LC-MS spectral data. The results of cytotoxicity evaluated by bioluminescence inhibition of bacterium Photobacterium leiognathi, strain Sh1 showed that compds.4.1, 4.6, and 6.1 were the most cytotoxic. Investigation of the antimicrobial and antifungal activity of amides 4-7 (concn. 5 mg/mL) was carried out by the stiff-plate agar-diffusion method. We found that the compds. possessed low (4.1, 4.7) antifungal activity against Candida tenuis and strong (4.21, 5.1, 5.9) or inefficient (4.7, 4.12, 4.16) activity against Aspergillus niger. Substances 5.1 and 5.9 slightly affected Mycobacterium luteum. Staphylococcus aureus was resistant to all obtained substances, and only the n-butyramide derivs. 7.1 and 7.5 inhibited the growth of Escherichia coli. Hence, there was no strong correlation between bioluminescence inhibition and antimicrobial activity of the investigated substances.
- 17Horne, W. S.; Yadav, M. K.; Stout, C. D.; Ghadiri, M. R. Heterocyclic Peptide Backbone Modifications in an α-Helical Coiled Coil. J. Am. Chem. Soc. 2004, 126, 15366– 15367, DOI: 10.1021/ja045040817https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXptlSgtrw%253D&md5=6f4573960370cdded62c2ca77ad25b04Heterocyclic Peptide Backbone Modifications in an α-Helical Coiled CoilHorne, W. Seth; Yadav, Maneesh K.; Stout, C. David; Ghadiri, M. RezaJournal of the American Chemical Society (2004), 126 (47), 15366-15367CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)In this paper, we present 1,2,3-triazole ε2-amino acids incorporated as a dipeptide surrogate at three positions in the sequence of a known α-helical coiled coil. Biophys. characterization indicates that the modified peptides retain much of the helical structure of the parent sequence, and that the thermodn. stability of the coiled coil depends on the position of the incorporation of the ε-residue. Crystal structures obtained for each peptide give insight into the chem. behavior and conformational preferences of the non-natural amino acid and show that the triazole ring can participate in the backbone hydrogen bonding of the α-helix as well as template an interhelical crossing between chains in the bundle.
- 18(a) Reddy, D. M.; Srinivas, J.; Chashoo, G.; Saxena, A. K.; Sampath Kumar, H. M. 4β-[(4-Alkyl)-1,2,3-triazol-1-yl] podophyllotoxins as anticancer compounds: Design, synthesis and biological evaluation. Eur. J. Med. Chem. 2011, 46, 1983– 1991, DOI: 10.1016/j.ejmech.2011.02.016There is no corresponding record for this reference.(b) Yoon, J.; Ryu, J.-S. A rapid synthesis of lavendustin-mimetic small molecules by click fragment assembly. Bioorg. Med. Chem. Lett. 2010, 20, 3930– 3935, DOI: 10.1016/j.bmcl.2010.05.01418bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXnsVWis7w%253D&md5=e07a4f2aa1c64bef25822ef2706547bfA rapid synthesis of lavendustin-mimetic small molecules by click fragment assemblyYoon, Jieun; Ryu, Jae-SangBioorganic & Medicinal Chemistry Letters (2010), 20 (13), 3930-3935CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Lavendustin-mimetic small mols. modifying the linker -CH2-NH- with an 1,2,3-triazole ring have been synthesized via a click chem. Two pharmacophoric fragments of lavendustin were varied to investigate chem. space and the auxophoric -CH2-NH- was altered to an 1,2,3-triazole for rapid click conjugation. The small mols. were evaluated against HCT116 colon cancer and CCRF-CEM leukemia cell lines. Among the 28 analogs, 3-phenylpropyl ester I inhibited CCRF-CEM leukemia cell growth with GI50 value of 0.9 μM.
- 19Giffin, M. J.; Heaslet, H.; Brik, A.; Lin, Y.-C.; Cauvi, G.; Wong, C.-H.; McRee, D. E.; Elder, J. H.; Stout, C. D.; Torbett, B. E. A Copper(I)-Catalyzed 1,2,3-Triazole Azide–Alkyne Click Compound Is a Potent Inhibitor of a Multidrug-Resistant HIV-1 Protease Variant. J. Med. Chem. 2008, 51, 6263– 6270, DOI: 10.1021/jm800149m19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtF2lsrvK&md5=c3ca2b1ae9e3a747ed7161715575f964A Copper(I)-Catalyzed 1,2,3-Triazole Azide-Alkyne Click Compound Is a Potent Inhibitor of a Multidrug-Resistant HIV-1 Protease VariantGiffin, Michael J.; Heaslet, Holly; Brik, Ashraf; Lin, Ying-Chuan; Cauvi, Gabrielle; Wong, Chi-Huey; McRee, Duncan E.; Elder, John H.; Stout, C. David; Torbett, Bruce E.Journal of Medicinal Chemistry (2008), 51 (20), 6263-6270CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Treatment with HIV-1 protease inhibitors, a component of highly active antiretroviral therapy (HAART), often results in viral resistance. Structural and biochem. characterization of a 6X protease mutant arising from in vitro selection with compd. 1, a C2-sym. diol protease inhibitor, has been previously described. We now show that compd. 2, a copper(I)-catalyzed 1,2,3-triazole derived compd. previously shown to be potently effective against wild-type protease (IC50 = 6.0 nM), has low nanomolar activity (IC50 = 15.7 nM) against the multidrug-resistant 6X protease mutant. Compd. 2 displays similar efficacy against wild-type and 6X HIV-1 in viral replication assays. While structural studies of compd. 1 bound to wild-type and mutant proteases revealed a progressive change in binding mode in the mutants, the 1.3 Å resoln. 6X protease-compd. 2 crystal structure reveals nearly identical interactions for 2 as in the wild-type protease complex with very little change in compd. 2 or protease conformation.
- 20Patpi, S. R.; Pulipati, L.; Yogeeswari, P.; Sriram, D.; Jain, N.; Sridhar, B.; Murthy, R.; Anjana Devi, T.; Kalivendi, S. V.; Kantevari, S. Design, Synthesis, and Structure-Activity Correlations of Novel Dibenzo[b,d]furan, Dibenzo[b,d]thiophene, and N-Methylcarbazole Clubbed 1,2,3-Triazoles as Potent Inhibitors of Mycobacterium tuberculosis. J. Med. Chem. 2012, 55, 3911– 3922, DOI: 10.1021/jm300125e20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XksVymurg%253D&md5=aa0a15ae22de7006b3a367fcaf49576bDesign, Synthesis, and Structure-Activity Correlations of Novel Dibenzo[b,d]furan, Dibenzo[b,d]thiophene, and N-Methylcarbazole Clubbed 1,2,3-Triazoles as Potent Inhibitors of Mycobacterium tuberculosisPatpi, Santhosh Reddy; Pulipati, Lokesh; Yogeeswari, Perumal; Sriram, Dharmarajan; Jain, Nishant; Sridhar, Balasubramanian; Murthy, Ramalinga; T, Anjana Devi; Kalivendi, Shasi Vardhan; Kantevari, SrinivasJournal of Medicinal Chemistry (2012), 55 (8), 3911-3922CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A mol. hybridization approach is an emerging structural modification tool to design new mols. with improved pharmacophoric properties. In this study, 1,2,3-triazole-based Mycobacterium tuberculosis inhibitors and synthetic and natural product-based tricyclic (carbazole, dibenzo[b,d]furan, and dibenzo[b,d]thiophene) antimycobacterial agents were integrated in one mol. platform to prep. various novel clubbed 1,2,3-triazole hybrids using click chem. Structure-activity correlations and in vitro activity against M. tuberculosis strain H37Rv of new analogs revealed the order: dibenzo[b,d]thiophene > dibenzo[b,d]furan > 9-methyl-9H-carbazole series. Some of the most potent M. tuberculosis inhibitors with MIC = 0.78 μg/mL (∼1.9 μM) displayed a low cytotoxicity and high selectivity index (50-255) against four different human cancer cell lines. These results together provided the potential importance of mol. hybridization and the development of triazole clubbed dibenzo[b,d]thiophene-based lead candidates to treat mycobacterial infections.
- 21De Simone, R.; Chini, M. G.; Bruno, I.; Riccio, R.; Mueller, D.; Werz, O.; Bifulco, G. Structure-Based Discovery of Inhibitors of Microsomal Prostaglandin E2Synthase–1, 5-Lipoxygenase and 5-Lipoxygenase-Activating Protein: Promising Hits for the Development of New Anti-inflammatory Agents. J. Med. Chem. 2011, 54, 1565– 1575, DOI: 10.1021/jm101238d21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXitVKqtbw%253D&md5=7e4379cce59ecf39290522c8238a3647Structure-Based Discovery of Inhibitors of Microsomal Prostaglandin E2 Synthase-1, 5-Lipoxygenase and 5-Lipoxygenase-Activating Protein: Promising Hits for the Development of New Anti-inflammatory AgentsDe Simone, Rosa; Chini, Maria Giovanna; Bruno, Ines; Riccio, Raffaele; Mueller, Daniela; Werz, Oliver; Bifulco, GiuseppeJournal of Medicinal Chemistry (2011), 54 (6), 1565-1575CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Microsomal prostaglandin E2 synthase (mPGES)-1 catalyzes the transformation of PGH2 to PGE2 that is involved in several pathologies like fever, pain, and inflammatory disorders. To identify novel mPGES-1 inhibitors, we used in silico screening to rapidly direct the synthesis, based on the copper-catalyzed 3 + 2 Huisgen's reaction (click chem.), of potential inhibitors. We designed 26 new triazole-based compds. in accordance with the pocket binding requirements of human mPGES-1. Docking results, in agreement with ligand efficiency values, suggested the synthesis of 15 compds. that at least in theory were shown to be more efficient in inhibiting mPGES-1. Biol. evaluation of these selected compds. has disclosed three new potential anti-inflammatory drugs: (I) compd. 4 displaying selectivity for mPGES-1 with an IC50 value of 3.2 μM, (II) compd. 20 that dually inhibits 5-lipoxygenase and mPGES-1, and (III) compd. 7 apparently acting as 5-lipoxygenase-activating protein inhibitor (IC50 = 0.4 μM).
- 22Banerji, B.; Killi, S. K.; Katarkar, A.; Chatterjee, S.; Tangella, Y.; Prodhan, C.; Chaudhuri, K. Neo-tanshinlactone D-ring modified novel analogues induce apoptosis in human breast cancer cell via DNA damage. Bioorg. Med. Chem. 2017, 25, 202– 212, DOI: 10.1016/j.bmc.2016.10.026There is no corresponding record for this reference.
- 23Viegas-Junior, C.; Barreiro, E. J.; Fraga, C. A. M. Molecular hybridization: a useful tool in the design of new drug prototypes. Bioorg. Med. Chem. 2007, 14, 1829– 1852, DOI: 10.2174/092986707781058805There is no corresponding record for this reference.
- 24Stamos, J.; Sliwkowski, M. X.; Eigenbrot, C. Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J. Biol. Chem. 2002, 277, 46265– 46272, DOI: 10.1074/jbc.m20713520024https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XovFKhsL4%253D&md5=c63c60b93756bd45fb2375c56ba38941Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitorStamos, Jennifer; Sliwkowski, Mark X.; Eigenbrot, CharlesJournal of Biological Chemistry (2002), 277 (48), 46265-46272CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)The crystal structure of the kinase domain from the epidermal growth factor receptor (EGFRK) including forty amino acids from the carboxyl-terminal tail has been detd. to 2.6-Å resoln., both with and without an EGFRK-specific inhibitor currently in Phase III clin. trials as an anti-cancer agent, erlotinib (OSI-774, CP-358,774, Tarceva). The EGFR family members are distinguished from all other known receptor tyrosine kinases in possessing constitutive kinase activity without a phosphorylation event within their kinase domains. Despite its lack of phosphorylation, we find that the EGFRK activation loop adopts a conformation similar to that of the phosphorylated active form of the kinase domain from the insulin receptor. Surprisingly, key residues of a putative dimerization motif lying between the EGFRK domain and carboxyl-terminal substrate docking sites are found in close contact with the kinase domain. Significant intermol. contacts involving the carboxyl-terminal tail are discussed with respect to receptor oligomerization.
- 25Towbin, H.; Staehelin, T.; Gordon, J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc. Natl. Acad. Sci. U. S. A. 1979, 76, 4350– 4354, DOI: 10.1073/pnas.76.9.435025https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1MXmtVKltLw%253D&md5=39eea3d100df7959e5d12e39e14cecbfElectrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: Procedure and some applicationsTowbin, Harry; Staehelin, Theophil; Gordon, JulianProceedings of the National Academy of Sciences of the United States of America (1979), 76 (9), 4350-4CODEN: PNASA6; ISSN:0027-8424.A method was devised for the electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets. The method results in quant. transfer of ribosomal proteins from gels contg. urea. For Na dodecyl sulfate gels, the original band pattern was obtained with no loss of resoln., but the transfer was not quant. The method allows detection of proteins by autoradiog. and is simpler than conventional procedures. The immobilized proteins were detectable by immunol. procedures. All addnl. binding capacity on the nitrocellulose was blocked with excess protein; then, a specific antibody was bound and, finally, a 2nd antibody directed against the 1st antibody. The 2nd antibody was wither radioactively labeled or conjugated to fluorescein or to peroxidase. The specific protein was then detected by either autoradiog., under UV light, or by the peroxidase reaction product, resp. In the latter case, as little as 100 pg of protein was clearly detectable.
- 26Lambert, A. J.; Brand, M. D. Superoxide production by NADH:ubiquinone oxidoreductase (complex I) depends on the pH gradient across the mitochondrial inner membrane. Biochem. J. 2004, 382, 511– 517, DOI: 10.1042/bj20040485There is no corresponding record for this reference.
- 27Dey, S. K.; Bose, D.; Hazra, A.; Naskar, S.; Nandy, A.; Munda, R. N.; Das, S.; Chatterjee, N.; Mondal, N. B.; Banerjee, S.; Saha, K. D. Cytotoxic activity and apoptosis-inducing potential of di-spiropyrrolidino and di-spiropyrrolizidino oxindole andrographolide derivatives. PLoS One 2013, 8, e58055, DOI: 10.1371/journal.pone.005805527https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXktlSrsLg%253D&md5=64ae726bf948e1fc8225ad1a9ae8f516Cytotoxic activity and apoptosis-inducing potential of di-spiropyrrolidino and di-spiropyrrolizidino oxindole andrographolide derivativesDey, Sumit Kumar; Bose, Dipayan; Hazra, Abhijit; Naskar, Subhendu; Nandy, Abhishek; Munda, Rudra Narayan; Das, Subhadip; Chatterjee, Nabanita; Mondal, Nirup Bikash; Banerjee, Sukdeb; Das Saha, KrishnaPLoS One (2013), 8 (3), e58055CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Anticancer role of andrographolide is well documented. To find novel potent derivs. with improved cytotoxicity than andrographolide on cancer cells, two series of di-spiropyrrolidino- and di-spiropyrrolizidino oxindole andrographolide derivs. prepd. by cyclo-addn. of azomethine ylide along with sarcosine or proline (viz. sarcosine and proline series resp.) and substitution of different functional groups (-CH3, -OCH3 and halogens) were examd. for their cytotoxic effect on a panel of six human cancer cell lines (colorectal carcinoma HCT116 cells, pancreatic carcinoma MiaPaCa-2 cells, hepatocarcinoma HepG2 cells, cervical carcinoma HeLa cells, lung carcinoma A549 and melanoma A375 cells). Except halogen substituted derivs. of proline series (viz. CY2, CY14 and CY15 for Br, Cl and I substitution resp.), none of the other derivs. showed improved cytotoxicity than andrographolide in the cancer cell lines examd. Order of cytotoxicity of the potent compds. is CY2>CY14>CY15>andrographolide. Higher toxicity was obsd. in HCT116, MiaPaCa-2 and HepG2 cells. CY2, induced death of HCT116 (GI50 10.5), MiaPaCa-2 (GI50 11.2) and HepG2 (GI50 16.6) cells were assocd. with cell rounding, nuclear fragmentation and increased percentage of apoptotic cells, cell cycle arrest at G1 phase, ROS generation and involvement of mitochondrial pathway. Upregulation of Bax, Bad, p53, caspases-3,-9 and cleaved PARP; downregulation of Bcl-2, cytosolic NF-κB p65, PI3K and p-Akt; translocation of P53/P21, NF-κB p65 were seen in CY2 treated HCT116 cells. Thus, three halogenated di-spiropyrrolizidino oxindole derivs. of andrographolide are found to be more cytotoxic than andrographolide in some cancer cells. The most potent deriv., CY2 induced death of the cancer cells involves ROS dependent mitochondrial pathway like andrographolide.
- 28Nandy, A.; Dey, S.; Das, S.; Munda, R.; Dinda, J.; Saha, K. Gold (I) N-heterocyclic carbene complex inhibits mouse melanoma growth by p53 upregulation. Mol. Cancer 2014, 13, 57, DOI: 10.1186/1476-4598-13-5728https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXivFWhtbc%253D&md5=40df17b4bddf6dce687596250172e457Gold (I) N-heterocyclic carbene complex inhibits mouse melanoma growth by p53 upregulationNandy, Abhishek; Dey, Sumit Kumar; Das, Sujata; Munda, Rudra Narayan; Dinda, Joydev; Das Saha, KrishnaMolecular Cancer (2014), 13 (), 57/1-57/14, 14 pp.CODEN: MCOACG; ISSN:1476-4598. (BioMed Central Ltd.)Background: Cancer treatment using gold (I) complexes is becoming popular. In this study, a gold (I) N-heterocyclic complex designated as complex 3 was synthesized, its cytotoxicity was examd., and its anti-melanoma activity was evaluated in vitro and in vivo. Methods: Viability of cancer cells was detd. by MTT assay upon treatment with various concns. of a gold (I) N-heterocyclic carbene complex (complex 3) in a dose and time dependent manner. Mouse melanoma cells B16F10 were selected for further apoptotic studies, including flowcytometric anal. of annexin binding, cell cycle arrest, intracellular ROS generation and loss in the mitochondrial membrane potential. ELISA based assays were done for caspase activities and western blots for detg. the expression of various survival and apoptotic proteins. Immunocytol. was performed to visualize the translocation of p53 to the nucleus. B16F10 cells were inoculated into mice and post tumor formation, complex 3 was administered. Immunohistol. was performed to det. the expressions of p53, p21, NF-κB (p65 and p50), MMP-9 and VEGF. Student's t test was used for detg. statistical significance. The survival rate data were analyzed by Kaplan-Meier plots. Results: Complex 3 markedly inhibited the growth of HCT 116, HepG2, and A549, and induced apoptosis in B16F10 cells with nuclear condensation, DNA fragmentation, externalization of phosphatidylserine, activation of caspase 3 and caspase 9, PARP cleavage, downregulation of Bcl-2, upregulation of Bax, cytosolic cytochrome c elevation, ROS generation, and mitochondrial membrane potential loss indicating the involvement of an intrinsic mitochondrial death pathway. Further, upregulation of p53, p-p53 (ser 15) and p21 indicated the role of p53 in complex 3 mediated apoptosis. The complex reduced tumor size, and caused upregulation of p53 and p21 along with downregulation of NF-κB (p65 and p50), VEGF and MMP-9. These results suggest that it induced anti-melanoma effect in vitro and in vivo by modulating p53 and other apoptotic factors. Conclusions: The gold (I) N-heterocyclic carbene complex (C22H26N6AuO2PF6) designated as complex 3 induced ROS and p53 dependent apoptosis in B16F10 cells involving the mitochondrial death pathway along with suppression of melanoma tumor growth by regulating the levels of pro and anti apoptotic factors (p53, p21, NF-κB, VEGF and MMP-9).
Supporting Information
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b01960.
1H NMR and 13C NMR spectra of all compounds and crystal data of compound 5c (PDF)
Crystallographic data of compound 5c (CIF)
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