Novel Enyne-Modified 1,4-Thiazepines as Epidermal Growth Factor Receptor Inhibitors: Anticancer and Computational Studies

1,4-Thiazepines (TZEPs) featuring enyne modifications represent promising candidates in cancer therapy. We synthesized novel TZEP derivatives and assessed their cytotoxicity, apoptosis induction, EGFR inhibition, and molecular interactions. TZEPs exhibited cytotoxic effects against cancer cell lines, with compounds TZEP6 and TZEP7 showing significant activity. Flow cytometry analysis revealed TZEP7-induced apoptosis across various cancer types. RT-qPCR analysis demonstrated downregulation of antiapoptotic Bcl-2, upregulation of pro-apoptotic Bax, and increased caspase levels following TZEP7 treatment. Additionally, TZEP7 inhibited EGFR kinase activity in cancer cells, with molecular docking confirming strong binding affinities to EGFRWT and mutant EGFRT790M. AdmetSAR analysis indicated favorable pharmacokinetic properties for TZEP7. These findings underscore the potential of enyne-modified TZEPs as selective cytotoxic agents with apoptotic and EGFR inhibitory activities, highlighting their significance in cancer therapy.