ABSTRACT The anticancer efficacy of 4‐aryl‐2‐hydrazinothiazole derivatives, which combine a thiazole known for its wide range of medicinal applications and a hydrazide/hydrazone structure known for its unique biological properties, has been determined in numerous studies. In this study, novel 2‐[4‐[(2‐(4‐substituted thiazol‐2‐yl)hydrazono)methyl]phenoxy]acetic acid derivatives (2a–l) were synthesized and evaluated for their anticancer activity in MCF‐7 breast cancer, A549 lung cancer, and L929 normal cell lines using cytotoxicity, apoptosis, and caspase‐3 activation assays. The compounds were found to exhibit high cytotoxicity, particularly showing more selective and high‐potential antiproliferative activity on the MCF‐7 cell line. In apoptosis studies, compounds 2c, 2d, and 2h caused programmed cell death in MCF‐7 cells exceeding 24%, close to cisplatin. Among these compounds, the derivative 2c containing 4‐methoxyphenyl caused caspase‐3 activation at a level similar to cisplatin. To conduct in silico studies of the compounds, molecular docking studies with the (4QTX) caspase‐3 enzyme, molecular dynamics simulation for three compounds (2d, 2g and 2l), and Density Functional Theory (DFT) studies were performed. These studies have shown that the carboxylate groups in the compounds form strong and stable interactions with Arg64 and Arg207.
Zeynep Zişan Demirci, Erol Akgün, G. Çiftçi et al.· Chemical Biology and Drug De...· 0 citations
To identify targeted cytotoxic agents for the treatment of non-small cell lung cancer (NSCLC), novel thiazolyl hydrazones (2a-t) were synthesized and evaluated for their cytotoxicity toward A549 human lung adenocarcinoma and L929 mouse embryonic fibroblast cells. Among these compounds, compound 2b exhibited the highest cytotoxic activity against A549 cells (IC50= 6.10 µM), followed by compounds 2g, 2k, 2r, 2f, 2o, 2e, 2s, and 2h, all of which were more potent than erlotinib (IC50 = 77.35 μM). In vitro mechanistic assays were conducted to assess their effects on apoptosis, cell cycle, epidermal growth factor receptor (EGFR), Akt, and signal transducer and activator of transcription 3 (STAT3). Flow cytometry analyses revealed that these agents induced apoptosis and G0/G1 cell cycle arrest, indicating that their cytotoxic effects are mediated through these mechanisms. Compound 2f was identified as the most promising compound, exhibiting selective cytotoxicity mediated by the concurrent inhibition of EGFR, Akt, and STAT3, with greater inhibitory potency toward EGFR and STAT3 relative to the EGFR TKI erlotinib and the STAT3 inhibitor C188-9. Compound 2e emerged as a potent dual EGFR/STAT3 inhibitor, exerting EGFR inhibitory activity comparable to that of erlotinib while exhibiting superior STAT3 inhibitory activity relative to C188-9. Compound 2b showed the highest cytotoxic potency against A549 cells, primarily through EGFR inhibition, with 8.3-fold greater activity than erlotinib. Compound 2r was identified as the most potent STAT3 inhibitor, exerting 10.8-fold higher activity than C188-9. These findings highlight the potential of thiazolyl hydrazones as targeted therapeutic agents, warranting further investigations for NSCLC treatment.
M. Altıntop, Ipek Ertorun, G. Çiftçi et al.· Bioorganic chemistry (Print)· 0 citations
