Development of thiazole-hydrazone hybrids for targeted therapy of non-small cell lung cancer.

Abstract

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.