Atmaca Harika, Çamlı Pulat Çisil, Ilhan Suleyman, Yilmaz Elif Serel, Zora Metin
Department of Biology, Faculty of Engineering and Natural Sciences, Manisa Celal Bayar University, 45140 Manisa, Turkey.
Applied Science Research Center, Manisa Celal Bayar University, 45140 Manisa, Turkey.
ACS Omega. 2024 Dec 26;10(1):821-832. doi: 10.1021/acsomega.4c07877. eCollection 2025 Jan 14.
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.
具有烯炔修饰的1,4-硫氮杂䓬（TZEPs）是癌症治疗中有前景的候选药物。我们合成了新型TZEP衍生物，并评估了它们的细胞毒性、诱导凋亡作用、表皮生长因子受体（EGFR）抑制作用以及分子相互作用。TZEPs对癌细胞系表现出细胞毒性作用，化合物TZEP6和TZEP7显示出显著活性。流式细胞术分析揭示了TZEP7在多种癌症类型中诱导凋亡。逆转录定量聚合酶链反应（RT-qPCR）分析表明，TZEP7处理后抗凋亡蛋白Bcl-2下调，促凋亡蛋白Bax上调，半胱天冬酶水平升高。此外，TZEP7抑制癌细胞中的EGFR激酶活性，分子对接证实其与野生型EGFR（EGFRWT）和突变型EGFR T790M具有很强的结合亲和力。ADMET SAR分析表明TZEP7具有良好的药代动力学性质。这些发现强调了烯炔修饰的TZEPs作为具有凋亡和EGFR抑制活性的选择性细胞毒性药物的潜力，突出了它们在癌症治疗中的重要性。
