College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China; State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, China.
College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China.
Bioorg Chem. 2021 Jan;106:104469. doi: 10.1016/j.bioorg.2020.104469. Epub 2020 Nov 10.
A series of novel 2-oxoquinoline derivatives containing arylaminothiazole were designed and synthesized as potential antitumor agents. The synthesized compounds were evaluated for their in vitro cytotoxicity activity against HeLa, NCI-H460, T24 and SKOV3 cancer cell lines using MTT assay. Among them, compound A7 exhibited the most potent activity against the test cancer cell lines, with the IC values ranged from 4.4 to 8.7 µM. The results of tubulin polymerization assay showed that compound A7 could inhibit tubulin polymerization in vitro. Meanwhile, molecular docking study revealed that A7 can bind to the colchicine site of tubulin and formed hydrogen bonds with key amino acid residues in the active site. Further mechanism study demonstrated that compound A7 blocked cell cycle arrest at G2/M phase, induced cell apoptosis and depolarized mitochondria of HeLa cells. Collectively, our findings suggest that A7 could serve as a promising lead for the development of more efficient microtubule polymerization inhibitors for cancer therapy.
一系列新型的含芳基氨噻唑的 2-氧代喹啉衍生物被设计和合成，作为潜在的抗肿瘤药物。合成的化合物通过 MTT 法评估其对 HeLa、NCI-H460、T24 和 SKOV3 癌细胞系的体外细胞毒性活性。其中，化合物 A7 对测试的癌细胞系表现出最强的活性，IC 值范围为 4.4 到 8.7µM。微管聚合试验结果表明，化合物 A7 能够在体外抑制微管聚合。同时，分子对接研究表明，A7 可以与微管的秋水仙碱结合部位结合，并与活性部位的关键氨基酸残基形成氢键。进一步的机制研究表明，化合物 A7 阻断了 HeLa 细胞的细胞周期停滞在 G2/M 期，诱导细胞凋亡和线粒体去极化。总之，我们的研究结果表明，A7 可能成为开发更有效的用于癌症治疗的微管聚合抑制剂的有前途的先导化合物。
