Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou, 510515, PR China.
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou, 510515, PR China.
Eur J Med Chem. 2020 Oct 15;204:112625. doi: 10.1016/j.ejmech.2020.112625. Epub 2020 Jul 19.
On the basis of our previous work, twenty-nine novel [1,2,4]triazolo[4,3-a]pyridines possessing 3,4,5-trimethoxylphenyl groups were designed, synthesized, and evaluated as tubulin polymerization inhibitors. The bioassay results revealed that some of the compounds displayed excellent antiproliferative efficacies in the nanomolar range against HeLa cells, and the most promising derivative 7i demonstrated almost comparable activity to that of the reference CA-4 and sixty-two fold more potent than the parent compound 6 with an IC value of 12 nM. Importantly, 7i exhibited high selectivity over the normal human embryonic kidney HEK-293 cells (IC > 100 μM). Further mechanism studies revealed that 7i significantly arrested cell cycle at G2/M phase, induced apoptosis with a dose-dependent manner, and disrupted microtubule networks. Additionally, the most active compound 7i effectively inhibited tubulin polymerization with a value similar to that of CA-4 (3.4 and 4.2 μM, respectively). Furthermore, molecular docking analysis suggested that 7i well occupied the colchicine binding pocket of tubulin. The present study highlights that compound 7i is a novel potential tubulin polymerization inhibitor and deserves further investigation for the treatment of cancers.
基于我们之前的工作，设计、合成并评价了 29 种新型[1,2,4]三唑并[4,3-a]吡啶类化合物，它们具有 3,4,5-三甲氧基苯基基团，作为微管蛋白聚合抑制剂。生物测定结果表明，一些化合物对 HeLa 细胞具有优异的纳摩尔范围的抗增殖活性，最有前途的衍生物 7i 的活性几乎与参比 CA-4 相当，与母体化合物 6 相比活性提高了 62 倍，IC 值为 12 nM。重要的是，7i 对正常的人胚肾 HEK-293 细胞具有高选择性（IC > 100 μM）。进一步的机制研究表明，7i 能显著将细胞周期阻滞在 G2/M 期，以剂量依赖性方式诱导细胞凋亡，并破坏微管网络。此外，最有效的化合物 7i 能有效抑制微管蛋白聚合，其活性与 CA-4 相似（分别为 3.4 和 4.2 μM）。此外，分子对接分析表明，7i 能很好地占据微管蛋白的秋水仙碱结合口袋。本研究强调，化合物 7i 是一种新型潜在的微管蛋白聚合抑制剂，值得进一步研究用于癌症的治疗。
