School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China.
School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China; International Healthcare Innovation Institute (Jiangmen), Jiangmen 529040, China.
Bioorg Med Chem Lett. 2021 May 15;40:127968. doi: 10.1016/j.bmcl.2021.127968. Epub 2021 Mar 19.
A series of 5-phenyloxazole-2-carboxylic acid derivatives were synthesized, and their structure-activity relationships (SARs) were studied. N,5-diphenyloxazole-2-carboxamides 6, 7, and 9, which mimicked ABT751, showed improved cytotoxicity compared with ABT751. Compound 9 exhibited the highest antiproliferative activities against Hela A549, and HepG2 cancer cell lines, with IC values of 0.78, 1.08, and 1.27 μM, respectively. Furthermore, compound 9 showed selectivity for human cancer cells over normal cells, and this selectivity was greater than those of ABT751 and colchicine. Preliminary mechanism studies suggested that compound 9 inhibited tubulin polymerization and led to cell cycle arrest at G/M phase. Molecular docking studies indicated that compound 9 bound to the colchicine binding site of tubulin. Our findings provided insights into useful SARs for further structural modification of inhibitors of tubulin polymerization.
我们合成了一系列 5-苯并恶唑-2-羧酸衍生物，并对其结构-活性关系（SAR）进行了研究。模拟 ABT751 的 N，5-二苯并恶唑-2-甲酰胺 6、7 和 9 显示出比 ABT751 更高的细胞毒性。化合物 9 对 Hela A549、HepG2 癌细胞系的增殖抑制活性最高，IC 值分别为 0.78、1.08 和 1.27 μM。此外，化合物 9 对人癌细胞的选择性高于正常细胞，且这种选择性大于 ABT751 和秋水仙碱。初步的机制研究表明，化合物 9 抑制微管蛋白聚合，并导致细胞周期停滞在 G/M 期。分子对接研究表明，化合物 9 结合到微管蛋白的秋水仙碱结合位点。我们的研究结果为进一步修饰微管蛋白聚合抑制剂提供了有用的 SAR。
