Key Laboratory of Biomedical Functional Materials, School of Science, China Pharmaceutical University, Nanjing, 211198, PR China; Department of Trauma Center, Affiliated Hospital of Nantong University, No.20 Xisi Road, Chongchuan District, Nantong City, Jiangsu Province, 226001, PR China.
Key Laboratory of Biomedical Functional Materials, School of Science, China Pharmaceutical University, Nanjing, 211198, PR China.
Eur J Med Chem. 2024 Mar 5;267:116177. doi: 10.1016/j.ejmech.2024.116177. Epub 2024 Jan 24.
As the basic unit of microtubules, tubulin is one of the most important targets in the study of anticarcinogens. A novel series of 3-amino-5-phenylpyrazole derivatives were designed and synthesized, and evaluates for their biological activities. Among them, a majority of compounds exerted excellent inhibitory activities against five cancer cell lines in vitro. Especially, compound 5b showed a strong antiproliferative activity against MCF-7 cells, with IC value of 38.37 nM. Further research indicated that compound 5b can inhibit the polymerization of tubulin targeting the tubulin colchicine-binding sites. Furthermore, 5b could arrest MCF-7 cells at the G2/M phase and induce MCF-7 cells apoptotic in a dose-dependent and time-dependent manners, and regulate the level of related proteins expression. Besides, compound 5b could inhibit the cancer cell migration and angiogenesis. In addition, 5b could inhibit tumor growth in MCF-7 xenograft model without obvious toxicity. All these results indicating that 5b could be a promising antitumor agent targeting tubulin colchicine-binding site and it was worth further study.
作为微管的基本单位，微管蛋白是抗癌药物研究中最重要的靶标之一。设计并合成了一系列新型的 3-氨基-5-苯基吡唑衍生物，并评估了它们的生物活性。其中，大多数化合物对五种癌细胞系具有优异的体外抑制活性。特别是，化合物 5b 对 MCF-7 细胞表现出强烈的增殖抑制活性，IC 值为 38.37 nM。进一步的研究表明，化合物 5b 可以通过靶向微管蛋白秋水仙碱结合位点抑制微管蛋白的聚合。此外，5b 可以剂量依赖性和时间依赖性地将 MCF-7 细胞阻滞在 G2/M 期并诱导 MCF-7 细胞凋亡，并调节相关蛋白表达水平。此外，化合物 5b 可以抑制癌细胞迁移和血管生成。另外，5b 可以在 MCF-7 异种移植模型中抑制肿瘤生长而没有明显的毒性。所有这些结果表明，5b 可能是一种有前途的靶向微管蛋白秋水仙碱结合位点的抗肿瘤药物，值得进一步研究。
