Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou 510515, PR China.
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou 510515, PR China.
Bioorg Med Chem Lett. 2020 Apr 15;30(8):127025. doi: 10.1016/j.bmcl.2020.127025. Epub 2020 Feb 11.
Twenty-six novel pyrazolo[3,4-b]pyridine-bridged analogues of combretastatin A-4 possessing 3,4,5-trimethoxylphenyl groups, were synthesized and evaluated for their antiproliferative and tubulin polymerization inhibitory activities. Preliminary biological evaluation demonstrated that some of the target compounds displayed significant antiproliferative effectagainst four different cell lines including MCF-7, MDA-MB-231, HeLa and Kyse150. The most active analogue 6n was found to induce HeLa cells arrest in the G2/M phase in a dose-dependent manner. Molecular modeling studies indicated that derivative 6n most likely occupies the colchicine site of tubulin. The initial results suggest that the 3,4,5-trimethoxyphenyl substituted pyrazolo[3,4-b]pyridine could serve as a promising scaffold for development of potent tubulin inhibitors as anticancer agents.
合成了 26 种新型吡唑并[3,4-b]吡啶桥联的 combretastatin A-4 类似物，这些类似物都含有 3,4,5-三甲氧基苯基基团，并对它们的抗增殖和微管蛋白聚合抑制活性进行了评估。初步的生物学评价表明，一些目标化合物对 MCF-7、MDA-MB-231、HeLa 和 Kyse150 四种不同细胞系表现出显著的抗增殖作用。最活跃的类似物 6n 被发现能以剂量依赖的方式诱导 HeLa 细胞在 G2/M 期停滞。分子模拟研究表明，衍生物 6n 很可能占据微管蛋白的秋水仙碱结合位点。初步结果表明，3,4,5-三甲氧基苯基取代的吡唑并[3,4-b]吡啶可以作为开发有效的微管蛋白抑制剂作为抗癌药物的有前途的支架。
