Synthesis, Characterization, and Anticancer Activity of Benzothiazole Aniline Derivatives and Their Platinum (II) Complexes as New Chemotherapy Agents.
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ABSTRACT:
SUBMITTER: Islam MK
PROVIDER: S-EPMC8399196 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cisplatin-type covalent chemotherapeutics are a cornerstone of modern medicinal oncology. However, these drugs remain encumbered with dose-limiting side effects and are susceptible to innate and acquired resistance. The bulk of platinum anticancer research has focused on Cisplatin and its derivatives. Here, we take inspiration from the design of platinum complexes and ligands used successfully with other metals to create six novel complexes. Herein, the synthesis, characterization, DNA binding affinities, and lipophilicity of a series of non-traditional organometallic Pt(II)-complexes are described. These complexes have a basic [Pt(PL)(AL)]Cl2 molecular formula which incorporates either 2-pyrrolidin-2-ylpyridine, 2-(1H-Imidazol-2-yl)pyridine, or 2-(2-pyridyl)benzimidazole as the PL; the AL is resolved diaminocyclohexane. Precursor [Pt(PL)(Cl)2] complexes were also characterized for comparison. While the cytotoxicity and DNA binding properties of the three precursors were unexceptional, the corresponding [Pt(PL)(AL)]2+ complexes were promising; they exhibited different DNA binding interactions compared with Cisplatin but with similar, if not slightly better, cytotoxicity results. Complexes with 2-pyrrolidin-2-ylpyridine or 2-(2-pyridyl)benzimidazole ligands had similar DNA binding properties to those with 2-(1H-Imidazol-2-yl)pyridine ligands but were not as cytotoxic to all cell lines. The variation in activity between cell lines was remarkable and resulted in significant selectivity indices in MCF10A and MCF-7 breast cancer cell lines, compared with previously described similar Pt(II) complexes such as 56MESS.
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Project description:Here, we describe the synthesis, characterization, and in vitro biological evaluation of a series of transition metal complexes containing benzothiazole aniline (BTA). We employed BTA, which is known for its selective anticancer activity, and a salen-type Schiff-based ligand to coordinate several transition metals to achieve selective and synergistic cytotoxicity. The compounds obtained were characterized by NMR spectroscopy, mass spectrometry, Fourier transform infrared spectroscopy, and elemental analysis. The compounds L, MnL, FeL, CoL, and ZnL showed promising in vitro cytotoxicity against cancer cells, and they had a lower IC50 than that of the clinically used cisplatin. In particular, MnL had synergistic cytotoxicity against liver, breast, and colon cancer cells. Moreover, MnL, CoL, and CuL promoted the production of reactive oxygen species in HepG2 tumor cell lines. The lead compound of this series, MnL, remained stable in physiological settings, and docking results showed that it interacted rationally with the minor groove of DNA. Therefore, MnL may serve as a viable alternative to platinum-based chemotherapy.
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Project description:Introduction: Cancer, a significant global health concern, necessitates innovative treatments. The pivotal role of chronic inflammation in cancer development underscores the urgency for novel therapeutic strategies. Benzothiazole derivatives exhibit promise due to their distinctive structures and broad spectrum of biological effects. This study aims to explore new anti-tumor small molecule drugs that simultaneously anti-inflammatory and anticancer based on the advantages of benzothiazole frameworks. Methods: The compounds were characterized by nuclear magnetic resonance (NMR), liquid chromatograph-mass spectrometer (LC-MS) and high performance liquid chromatography (HPLC) for structure as well as purity and other related physicochemical properties. The effects of the compounds on the proliferation of human epidermoid carcinoma cell line (A431) and human non-small cell lung cancer cell lines (A549, H1299) were evaluated by MTT method. The effect of compounds on the expression levels of inflammatory factors IL-6 and TNF-α in mouse monocyte macrophages (RAW264.7) was assessed using enzyme-linked immunosorbent assay (ELISA). The effect of compounds on apoptosis and cell cycle of A431 and A549 cells was evaluated by flow cytometry. The effect of compounds on A431 and A549 cell migration was evaluated by scratch wound healing assay. The effect of compounds on protein expression levels in A431 and A549 cells was assessed by Western Blot assay. The physicochemical parameters, pharmacokinetic properties, toxicity and drug similarity of the active compound were predicted using Swiss ADME and admetSAR web servers. Results: Twenty-five novel benzothiazole compounds were designed and synthesized, with their structures confirmed through spectrogram verification. The active compound 6-chloro-N-(4-nitrobenzyl) benzo[d] thiazol-2-amine (compound B7) was screened through a series of bioactivity assessments, which significantly inhibited the proliferation of A431, A549 and H1299 cancer cells, decreased the activity of IL-6 and TNF-α, and hindered cell migration. In addition, at concentrations of 1, 2, and 4 μM, B7 exhibited apoptosis-promoting and cell cycle-arresting effects similar to those of the lead compound 7-chloro-N-(2, 6-dichlorophenyl) benzo[d] thiazole-2-amine (compound 4i). Western blot analysis confirmed that B7 inhibited both AKT and ERK signaling pathways in A431 and A549 cells. The prediction results of ADMET indicated that B7 had good drug properties. Discussion: This study has innovatively developed a series of benzothiazole derivatives, with a focus on compound B7 due to its notable dual anticancer and anti-inflammatory activities. B7 stands out for its ability to significantly reduce cancer cell proliferation in A431, A549, and H1299 cell lines and lower the levels of inflammatory cytokines IL-6 and TNF-α. These results position B7B7 as a promising candidate for dual-action cancer therapy. The study's mechanistic exploration, highlighting B7's simultaneous inhibition of the AKT and ERK pathways, offers a novel strategy for addressing both the survival mechanisms of tumor cells and the inflammatory milieu facilitating cancer progression.
| S-EPMC10982501 | biostudies-literature
Project description:During the last five decades, a large number of BT (Benzothiazole) derivatives formed one of the eligible structures in medicinal chemistry as anticancer agents. Most of the studies reveal that various substitutions at specific positions on BT scaffold modulate the antitumor property. The potential of BTs encouraged us to synthesize a number of new 2-((5-substitutedbenzothiazol-2-yl)thio)-N’-(2-(4-(substitutedphenyl)ethylidene)acetohydrazide derivatives and investigate their probable anticancer activity. 4-Substitued benzaldehyde derivatives (1a⁻1e) were afforded by the reaction of appropriate secondary amine and 4-fluorobenzaldehyde in DMF. Equimolar quantitates of 5-substitutedbenzothiazole-2-thiol, ethyl chloroacetate and K₂CO₃ were refluxed in acetone to obtain 2-((5-substitutedbenzothiazol-2-yl)thio)acetate derivatives (2a,2b), which reacted with excess of hydrazine hydrate to get 2-((5-substitutebenzothiazol-2-yl)thio)acetohydrazides (3a,3b). In the last step, 2-((5-substitutedbenzothiazol-2-yl)thio)-N’-(4-substitutedbenzylidene)acetohydrazide derivatives (4a⁻4j) were synthesized by the reaction of 1a⁻1e and 3a⁻3b in EtOH. The anticancer activity of target compounds was evaluated in three steps. First, an MTT test (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) was performed to observe cytotoxic activity of the compounds against carcinogenic C6 (Rat brain glioma cell line), A549 (Human lung adenocarcinoma epithelial cell line), MCF-7 (Human breast adenocarcinoma cell line), and HT-29 (Human colorectal adenocarcinoma cell line) cancer cell lines. Healthy NIH3T3 (Mouse embryo fibroblast cell line) cells were also subjected to MTT assay to determine selectivity of the compounds towards carcinogenic cell lines. Secondly, inhibitory effects of selected compounds 4d, 4e, and 4h on DNA synthesis of C6 cells were investigated. Finally, flow cytometric analysis were performed to identify the death pathway of the carcinogenic cells.
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Project description:A series of Pt(II) complexes trans-[Pt(PPh2 allyl)2 (κ1 -S-SR)2 ], 1, PPh2 allyl=allyldiphenylphosphine, SR=pyridine-2-thiol (Spy, 1 a), 5-(trifluoromethyl)-pyridine-2-thiol (SpyCF3 -5, 1 b), pyrimidine-2-thiol (SpyN, 1 c), benzothiazole-2-thiol (Sbt, 1 d), benzimidazole-2-thiol (Sbi, 1 e), were synthesized. They were characterized by NMR, HR ESI-MS, and X-ray crystallography. Treatment of human cancer cell lines (A549, SKOV3, MCF-7) with these complexes resulted in promising antitumor effects in comparison with cisplatin. These compounds showed suitable selectivity between tumorigenic and non-tumorigenic (MCF-10 A) cell lines. Analyses of cell cycle progression and apoptosis were conducted for 1 a, the most cytotoxic compound, to screen dose/time response and to study the antiproliferative mechanism. An electrophoresis mobility shift assay was performed to assess the direct interaction of 1 a with DNA and the strong genotoxic ability was indicated through the comet assay method.
| S-EPMC7108934 | biostudies-literature
Project description:Despite extensive studies and the great variety of existing anticancer agents, cancer treatment remains an aggravating and challenging problem. Therefore, the development of novel anticancer drugs with a better therapeutic profile and fewer side effects to combat this persistent disease is still necessary. In this study, we report a novel series of benzothiazole and chromone derivatives that were synthesized and evaluated for their anticancer activity as an inhibitor of ATR kinase, a master regulator of the DDR pathway. The cell viability of a set of 25 compounds was performed using MTT assay in HCT116 and HeLa cell lines, involving 72 h incubation of the compounds at a final concentration of 10 µM. Cells incubated with compounds 2c, 7h and 7l were found to show viability ≤50%, and were taken forward for dose-response studies. Among the tested compounds, three of them (2c, 7h and 7l) showed higher potency, with compound 7l exhibiting the best IC50 values in both the cell lines. Compounds 2c and 7l were found to be equally cytotoxic towards both the cell lines, namely, HCT116 and HeLa, while compound 7h showed better cytotoxicity towards HeLa cell line. For these three compounds, an immunoblot assay was carried out in order to analyze the inhibition of phosphorylation of Chk1 at Ser 317 in HeLa and HCT116 cells. Compound 7h showed inhibition of pChk1 at Ser 317 in HeLa cells at a concentration of 3.995 µM. Further analysis for Chk1 and pChk1 expression was carried out in Hela cells by treatment against all the three compounds at a range of concentrations of 2, 5 and 10 µM, wherein compound 7h showed Chk1 inhibition at 2 and 5 µM, while pChk1 expression was observed for compound 7l at a concentration of 5 µM. To support the results, the binding interactions of the compounds with the ATR kinase domain was studied through molecular docking, wherein compounds 2c, 7h and 7l showed binding interactions similar to those of Torin2, a known mTOR/ATR inhibitor. Further studies on this set of molecules is in progress for their specificity towards the ATR pathway.
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Project description:Yeast homozygous and essential heterozygous deletion mutants were screened against novel platinum-containing compounds
2012-08-28 | E-MTAB-1267 | biostudies-arrayexpress
Project description:A series of coordination gold(III), palladium(II), and platinum(II) complexes with a luminescent iminophosphorane ligand derived from 8-aminoquinoline [Ph3P=N-C9H6N] (1), have been synthesized and structurally characterized. The coordination palladium(II) and platinum(II) compounds can evolve further, under appropriate conditions, to give stable cyclometalated endo species [M{κ3-C,N,N-C6H4(PPh2=N-8-C9H6N}Cl] (M = Pd, Pt) by C-H activation of the phenyl group of the PPh 3 fragment. Iminophosphorane 1 and the new metallic complexes are luminescent in DMSO or DMSO:H2O (1:1 mixture) solutions at RT. The compounds have been evaluated for their antiproliferative properties in a human ovarian cancer cell line (A2780S), in human lung cancer cells (A-549) and in a non-tumorigenic human embryonic kidney cell line (HEK-293T). Most compounds have been more toxic to the ovarian cancer cell line than to the non-tumorigenic cell line. The new complexes interact with human serum albumin (HSA) faster than cisplatin. Studies of the interactions of the compounds with DNA indicate that, in some cases, they exert anticancer effects in vitro based on different mechanisms of action with respect to cisplatin.
| S-EPMC5029859 | biostudies-literature
Project description:New palladium (Pd)II and platinum (Pt)II complexes (C1-C5) from the Schiff base ligands, R-(phenyl)methanamine (L1), R-(pyridin-2-yl)methanamine (L2), and R-(furan-2-yl)methanamine (L3) (R-(E)-N-((1H-pyrrol-2-yl) methylene)) are herein reported. The complexes (C1-C5) were characterized by FTIR, 1H and 13C NMR, UV-vis, and microanalyses. Single-crystal X-ray crystallographic analysis was performed for the two ligands (L1-L2) and a Pt complex. Both L1 and L2 belong to P21/n monoclinic and P-1 triclinic space systems, respectively. The complex C5 belongs to the P21/c monoclinic space group. The investigated molar conductivity of the complexes in DMSO gave the range 4.0-8.8 μS/cm, suggesting neutrality, with log P values ≥ 1.2692 ± 0.004, suggesting lipophilicity. The anticancer activity and mechanism of the complexes were investigated against various human cancerous (Caco-2, HeLa, HepG2, MCF-7, and PC-3) and noncancerous (MCF-12A) cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Apopercentage assays, respectively. C5 demonstrated strong DNA-binding affinity for calf thymus DNA (CT-DNA) with a binding constant of 8.049 × 104 M-1. C3 reduced cell viability of all the six cell lines, which included five cancerous cell lines, by more than 80%. The C5 complex also demonstrated remarkably high selectivity with no cytotoxic activity toward the noncancerous breast cell line but reduced the viability of the five cancerous cell lines, which included one breast cancer cell line, by more than 60%. Further studies are required to evaluate the selective toxicity of these two complexes and to fully understand their mechanism of action.
| S-EPMC7330904 | biostudies-literature
Project description:Although cisplatin is considered as an effective anti-cancer agent, it has shown limitations and may produce toxicity in patients. Therefore, we synthesized two cis-dichlorideplatinum(II) compounds (13 and 14) composed of meta- and para-N,N-diphenyl pyridineamine ligands through a reaction of the amine precursors and PtCl2 with respective yields of 16 and 47 %. We hypothesized that compounds 13 and 14, with lipophilic ligands, should transport efficiently in cancer cells and demonstrate more effectiveness than cisplatin. When tested for biological activity, compounds 13 and 14 were found to inhibit the growth of MCF 7 and MDA-MB-231 cells (IC50s 1 ± 0.4 µM and 1 ± 0.2 µM for 13 and 14, respectively, and IC50 7.5 ± 1.3 µM for compound 13 and 1 ± 0.3 µM for compound 14). Incidentally, these doses were found to be lower than cisplatin doses (IC50 5 ± 0.7 µM for MCF 7 and 10 ± 1.1 µM for MDA-MB-231). Similar to cisplatin, 13 and 14 interacted with DNA and induced apoptosis. However, unlike cisplatin, they blocked the migration of MDA-MB-231 cells suggesting that in addition to apoptotic and DNA-binding capabilities, these compounds are useful in blocking the metastatic migration of breast cancer cells. To delineate the mechanism of action, computer-aided analyses (DFT calculations) were conducted for compound 13. Results indicate that in vivo, the pyridineamine ligands are likely to dissociate from the complex, forming a platinum DNA adduct with anti-proliferative activity. These results suggest that complexes 13 and 14 hold promise as potential anti-cancer agents.
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