Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia, 61519, Egypt.
Pharmacology and Experimental Oncology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, 11796, Egypt; Pharmacotherapy Department, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Eur J Med Chem. 2018 May 10;151:705-722. doi: 10.1016/j.ejmech.2018.03.073. Epub 2018 Mar 27.
A series of novel 1, 2, 4-triazole/chalcone hybrids was prepared and identified with different spectroscopic techniques. The prepared compounds showed remarkable cytotoxic activity against different cancer cell lines. Compounds 24, 25, 27, 41 and 47 had shown the highest cytotoxicity among the tested compounds against human lung adenocarcinoma A549 cells with IC ranging from 4.4 to 16.04 μM compared to cisplatin with IC of 15.3 μM. Flow cytometric analysis of the tested compounds showed an increase in the number of apoptotic cells in a dose-dependent manner. The further mechanistic study demonstrated that 1, 2, 4-triazole-chalcone hybrids induced apoptosis via increased level of proapoptotic protein Bax, release of cytochrome c from mitochondria and activation of caspase-3/8/9 proteins. However, general caspase inhibition by the pan-caspase inhibitor, z-VAD-fmk, significantly decreased the apoptosis induced by the tested hybrids, suggesting dependency of apoptosis on activation of the caspase-3 pathway.
一系列新型 1,2,4-三唑/查耳酮杂合体被制备并通过不同的光谱技术进行了鉴定。所制备的化合物对不同的癌细胞系表现出显著的细胞毒性。在测试的化合物中，化合物 24、25、27、41 和 47 对人肺腺癌细胞 A549 的细胞毒性最高，IC 范围为 4.4 至 16.04 μM，与顺铂的 IC 为 15.3 μM 相比。对测试化合物的流式细胞术分析表明，凋亡细胞的数量呈剂量依赖性增加。进一步的机制研究表明，1,2,4-三唑-查耳酮杂合体通过增加促凋亡蛋白 Bax 的水平、线粒体中细胞色素 c 的释放以及激活 caspase-3/8/9 蛋白诱导细胞凋亡。然而，通用半胱天冬酶抑制剂 z-VAD-fmk 显著降低了测试杂合体诱导的细胞凋亡，表明凋亡依赖于 caspase-3 途径的激活。
