Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470, Eskişehir, Turkey.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470, Eskişehir, Turkey.
Eur J Med Chem. 2018 Jul 15;155:905-924. doi: 10.1016/j.ejmech.2018.06.049. Epub 2018 Jun 22.
In the current work, new 1,3,4-oxadiazole derivatives were synthesized and investigated for their cytotoxic effects on A549 human lung adenocarcinoma, C6 rat glioma and NIH/3T3 mouse embryonic fibroblast cell lines. Compounds 2, 6 and 9 were found to be the most potent anticancer agents against A549 and C6 cell lines and therefore their effects on apoptosis, caspase-3 activation, Akt, FAK, mitochondrial membrane potential and ultrastructural morphological changes were evaluated. N-(5-Nitrothiazol-2-yl)-2-[[5-[((5,6,7,8-tetrahydronaphthalen-2-yl)oxy)methyl]-1,3,4-oxadiazol-2-yl]thio]acetamide (9) increased early and late apoptotic cell population in A549 and C6 cells more than cisplatin and caused more mitochondrial membrane depolarization in both cell lines than cisplatin. On the other hand, N-(6-methoxybenzothiazol-2-yl)-2-[[5-[((5,6,7,8-tetrahydronaphthalen-2-yl)oxy)methyl]-1,3,4-oxadiazol-2-yl]thio]acetamide (6) caused higher caspase-3 activation than cisplatin in both cell lines. Compound 6 showed significant Akt inhibitory activity in both cell lines. Moreover, compound 6 significantly inhibited FAK (Phospho-Tyr397) activity in C6 cell line. Molecular docking simulations demonstrated that compound 6 fitted into the active sites of Akt and FAK with high affinity and substrate-specific interactions. Furthermore, compounds 2, 6 and 9 caused apoptotic morphological changes in both cell lines obtained from micrographs by transmission electron microscopy. A computational study for the prediction of ADME properties of all compounds was also performed. These compounds did not violate Lipinski's rule, making them potential orally bioavailable anticancer agents.
在当前的工作中，我们合成了新的 1,3,4-噁二唑衍生物，并研究了它们对 A549 人肺腺癌细胞、C6 大鼠神经胶质瘤细胞和 NIH/3T3 小鼠胚胎成纤维细胞系的细胞毒性作用。发现化合物 2、6 和 9 对 A549 和 C6 细胞系具有最强的抗癌活性，因此评估了它们对细胞凋亡、半胱天冬酶-3 激活、Akt、FAK、线粒体膜电位和超微结构形态变化的影响。N-(5-硝基噻唑-2-基)-2-[[5-[[(5,6,7,8-四氢萘-2-基)氧基]甲基]-1,3,4-噁二唑-2-基]硫代]乙酰胺（9）使 A549 和 C6 细胞中的早期和晚期凋亡细胞群体增加比顺铂更多，并导致这两种细胞系中的线粒体膜去极化比顺铂更多。另一方面，N-(6-甲氧基苯并噻唑-2-基)-2-[[5-[[(5,6,7,8-四氢萘-2-基)氧基]甲基]-1,3,4-噁二唑-2-基]硫代]乙酰胺（6）使两种细胞系中的半胱天冬酶-3 激活比顺铂更高。化合物 6 在两种细胞系中均显示出显著的 Akt 抑制活性。此外，化合物 6 显著抑制 C6 细胞系中的 FAK（磷酸化 Tyr397）活性。分子对接模拟表明，化合物 6 与 Akt 和 FAK 的活性部位具有高亲和力和底物特异性相互作用。此外，化合物 2、6 和 9 使两种细胞系的凋亡形态发生变化，这是通过透射电子显微镜从显微照片中获得的。还对所有化合物的 ADME 性质进行了预测计算研究。这些化合物没有违反 Lipinski 规则，使它们成为有潜力的口服生物可用的抗癌药物。
