School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China.
School of Medicine, Hubei Polytechnic University, Huangshi 435003, China.
Bioorg Med Chem. 2021 Sep 15;46:116376. doi: 10.1016/j.bmc.2021.116376. Epub 2021 Aug 23.
A series of acridine and quinoline derivatives were designed and synthesized based on our previous work as novel tubulin inhibitors targeting the colchicine binding site. Among them, compound 3b exhibited the highest antiproliferative activity with an IC of 261 nM against HepG-2 cells (the most sensitive cell line). In addition, compound 3b was able to suppress the formation of HepG-2 colonies. Mechanism studies revealed that compound 3b effectively inhibited tubulin polymerization in vitro and disrupted microtubule dynamics in HepG-2 cells. Furthermore, compound 3b inhibited the migration of cancer cells in a dose dependent manner. Moreover, compound 3b induced cell cycle arrest in G2/M phase and led to cell apoptosis. Finally, docking studies demonstrated that compound 3b fitted nicely in the colchicine binding site of tubulin and overlapped well with CA-4. Collectively, these results suggested that compound 3b represents a novel tubulin inhibitor deserving further investigation.
基于我们之前的工作，我们设计并合成了一系列吖啶和喹啉衍生物，作为新型微管蛋白抑制剂，靶向秋水仙碱结合位点。其中，化合物 3b 对 HepG-2 细胞（最敏感的细胞系）表现出最高的抗增殖活性，IC 为 261 nM。此外，化合物 3b 能够抑制 HepG-2 集落的形成。机制研究表明，化合物 3b 能够有效抑制体外微管蛋白聚合，并破坏 HepG-2 细胞中的微管动力学。此外，化合物 3b 能够以剂量依赖的方式抑制癌细胞的迁移。此外，化合物 3b 诱导细胞周期停滞在 G2/M 期并导致细胞凋亡。最后，对接研究表明，化合物 3b 很好地适合于微管蛋白的秋水仙碱结合位点，并与 CA-4 很好地重叠。总之，这些结果表明化合物 3b 代表了一种新型的微管蛋白抑制剂，值得进一步研究。
