Medicinal Chemistry and Biotechnology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India; Department of Chemistry, Osmania University, Hyderabad 500007, Telangana, India.
Medicinal Chemistry and Biotechnology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
Bioorg Chem. 2019 Mar;83:535-548. doi: 10.1016/j.bioorg.2018.11.002. Epub 2018 Nov 3.
A library of 1-benzyl-N-(2-(phenylamino)pyridin-3-yl)-1H-1,2,3-triazole-4-carboxamides (7a-al) have been designed, synthesized and screened for their anti-proliferative activity against some selected human cancer cell lines namely DU-145, A-549, MCF-7 and HeLa. Most of them have shown promising cytotoxicity against lung cancer cell line (A549), amongst them 7f was found to be the most potent anti-proliferative congener. Furthermore, 7f exhibited comparable tubulin polymerization inhibition (IC value 2.04 µM) to the standard E7010 (IC value 2.15 µM). Moreover, flow cytometric analysis revealed that this compound induced apoptosis via cell cycle arrest at G/M phase in A549 cells. Induction of apoptosis was further observed by examining the mitochondrial membrane potential and was also confirmed by Hoechst staining as well as Annexin V-FITC assays. Furthermore, molecular docking studies indicated that compound 7f binds to the colchicine binding site of the β-tubulin. Thus, 7f exhibits anti-proliferative properties by inhibiting the tubulin polymerization through the binding at the colchicine active site and by induction of apoptosis.
设计、合成并筛选了一系列 1-苄基-N-(2-(苯氨基)吡啶-3-基)-1H-1,2,3-三唑-4-甲酰胺（7a-al）库，以评估它们对某些选定的人类癌细胞系（即 DU-145、A-549、MCF-7 和 HeLa）的抗增殖活性。其中大多数对肺癌细胞系（A549）表现出有希望的细胞毒性，其中 7f 被发现是最有效的增殖抑制剂。此外，7f 表现出与标准药物 E7010 相当的微管蛋白聚合抑制作用（IC 值为 2.04µM）。此外，流式细胞术分析显示，该化合物通过在 A549 细胞中使细胞周期停滞在 G/M 期诱导细胞凋亡。通过检查线粒体膜电位进一步观察到凋亡的诱导，并用 Hoechst 染色和 Annexin V-FITC 测定也得到了证实。此外，分子对接研究表明，化合物 7f 结合到微管蛋白的秋水仙碱结合位点。因此，7f 通过与秋水仙碱活性位点结合抑制微管蛋白聚合，并通过诱导细胞凋亡来发挥抗增殖作用。
