Li Gang, Wu Jia-Qiang, Cai Xiaojia, Guan Wen, Zeng Zhijun, Ou Yanghui, Wu Xiaoyun, Li Jiayu, Fang Xiangxiang, Liu Jinling, Zhang Yali, Wang Huamin, Yin Canqiang, Yao Hongliang
Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, Guangdong, 510260, China.
School of Biotechnology and Health Sciences, Wuyi University, 22 Dongchengcun, Jiangmen, 529020, China.
Eur J Med Chem. 2023 Apr 5;252:115284. doi: 10.1016/j.ejmech.2023.115284. Epub 2023 Mar 16.
A series of diaryl heterocyclic analogues were designed and synthesized as tubulin polymerization inhibitors. Among them, compound 6y showed the highest antiproliferative activity against HCT-116 colon cancer cell line with an IC values of 2.65 μM. Compound 6y also effectively inhibited tubulin polymerization in vitro (IC of 10.9 μM), and induced HCT-116 cell cycle arrest in G2/M phase. In addition, compound 6y exhibited high metabolic stability on human liver microsomes (T = 106.2 min). Finally, 6y was also effective in suppressing tumor growth in a HCT-116 mouse colon model without apparent toxicity. Collectively, these results suggest that 6y represents a new class of tubulin inhibitors deserving further investigation.
设计并合成了一系列二芳基杂环类似物作为微管蛋白聚合抑制剂。其中，化合物6y对HCT-116结肠癌细胞系表现出最高的抗增殖活性，IC值为2.65 μM。化合物6y在体外也能有效抑制微管蛋白聚合（IC为10.9 μM），并诱导HCT-116细胞周期停滞在G2/M期。此外，化合物6y在人肝微粒体上表现出较高的代谢稳定性（T = 106.2分钟）。最后，6y在HCT-116小鼠结肠癌模型中也能有效抑制肿瘤生长，且无明显毒性。总体而言，这些结果表明6y代表了一类值得进一步研究的新型微管蛋白抑制剂。
