Synthesis, Biological Evaluation, and Molecular Docking of Arylpyridines as Antiproliferative Agent Targeting Tubulin
Synthesis, Biological Evaluation, and Molecular Docking of Arylpyridines as Antiproliferative Agent Targeting Tubulin
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作为靶向微管蛋白的抗增殖剂的芳基吡啶的合成、生物学评价和分子对接
DOI：
10.1021/acsmedchemlett.0c00278
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发表时间：
2020-08-13
影响因子：
4.2
通讯作者：
Zhou, Zhong-Zhen
中科院分区：
文献类型：
--
作者：
He, JiaPeng;Zhang, Mao;Zhou, Zhong-Zhen
将不同的药效基团模拟到一个支架中是一种很有前途的结构修饰工具，可用于设计具有增强生物特性的新药物。为了继续我们对微管蛋白抑制剂的研究，本文描述了芳基吡啶衍生物 (9-29) 的合成和生物学评价。在这些化合物中，吡啶环2位上带有苯并[d]咪唑侧链的6-芳基吡啶(13-23)表现出针对HT-29细胞的选择性抗增殖活性。更有趣的是，带有苯并[d]咪唑和苯并[d]恶唑侧链的2-三甲氧基苯基吡啶25、27和29对所有测试的癌细胞系表现出更广谱的抗肿瘤活性。带有6-甲氧基苯并[d]恶唑基团的29对A549和U251细胞表现出与考布他汀A-4(CA-4)相当的活性，并且比CA-4和5-Fu具有更低的细胞毒性。进一步的研究表明，29表现出很强的微管蛋白聚合抑制活性（IC50=2.1μM），并有效地结合在秋水仙碱结合位点上，并通过破坏微管网络将A549的细胞周期阻滞在G2/M期。
Mimicking different pharmacophoric units into one scaffold is a promising structural modification tool to design new drugs with enhanced biological properties. To continue our research on the tubulin inhibitors, the synthesis and biological evaluation of arylpyridine derivatives (9-29) are described herein. Among these compounds, 6-arylpyridines (13-23) bearing benzo[d]imidazole side chains at the 2-position of pyridine ring displayed selective antiproliferative activities against HT-29 cells. More interestingly, 2-trimethoxyphenylpyridines 25, 27, and 29 bearing benzo[d]imidazole and benzo[d]oxazole side chains displayed more broad-spectrum antitumor activities against all tested cancer cell lines. 29 bearing a 6-methoxybenzo[d]oxazole group exhibited comparable activities against A549 and U251 cells to combretastatin A-4 (CA-4) and lower cytotoxicities than CA-4 and 5-Fu. Further investigations revealed 29 displays strong tubulin polymerization inhibitory activity (IC50 = 2.1 mu M) and effectively binds at the colchicine binding site and arrests the cell cycle of A549 in the G2/M phase by disrupting the microtubules network.