发现具有氨基侧链的多甲氧基苯基吡啶作为微管蛋白秋水仙碱结合位点抑制剂。
Discovery of polymethoxyphenyl-pyridines bearing amino side chains as tubulin colchicine-binding site inhibitors.
机构信息
Innovation Program of Drug Research on Neurological and Metabolic Diseases, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Innovation Program of Drug Research on Neurological and Metabolic Diseases, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Clinical Pharmacy Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
出版信息
Bioorg Med Chem. 2022 Nov 1;73:117007. doi: 10.1016/j.bmc.2022.117007. Epub 2022 Sep 15.
Nineteen TH03 analogues were designed and synthesized as tubulin colchicine-binding site inhibitors with potent antiproliferative activities. Among these compounds, 3,5-dimethoxyphenylpyridines 8j bearing a 4-methoxybenzyl aniline side-chain displayed the best antiproliferative activities against glioma (U87MG and U251). In addition, the trimethoxyphenylpyridine 8o bearing a 4-methyl-N-methyl aniline side-chain showed the best antiproliferative activities against colon carcinoma and lung cancer with the lowest IC value (0.09 µM < IC < 0.86 µM). Compared with CA-4, Compounds 8j and 8o displayed lower cytotoxicities toward normal cells but higher antiproliferative activities against RKO (IC = 0.15 µM and 0.09 µM respectively), NCI-H1299 (IC = 0.73 µM and 0.14 µM respectively), and A549 cells (IC = 0.86 µM and 0.37 µM respectively). Further investigations revealed that 8o shows higher tubulin polymerization inhibitory activity (IC = 3.1 ± 0.5 µM) than colchicine (IC = 8.6 ± 0.2 µM), and induced cell cycle arrest at the G2/M phase and cellular apoptosis through disrupting the microtubule network.
设计并合成了 19 种 TH03 类似物作为微管秋水仙碱结合位点抑制剂，具有很强的抗增殖活性。在这些化合物中，带有 4-甲氧基苄基苯胺侧链的 3,5-二甲氧基苯基吡啶 8j 对神经胶质瘤（U87MG 和 U251）显示出最好的抗增殖活性。此外，带有 4-甲基-N-甲基苯胺侧链的三甲氧基苯基吡啶 8o 对结肠癌和肺癌显示出最好的抗增殖活性，其最低 IC 值（0.09 µM < IC < 0.86 µM）。与 CA-4 相比，化合物 8j 和 8o 对正常细胞的细胞毒性较低，但对 RKO（IC = 0.15 µM 和 0.09 µM）、NCI-H1299（IC = 0.73 µM 和 0.14 µM）和 A549 细胞（IC = 0.86 µM 和 0.37 µM）的抗增殖活性更高。进一步的研究表明，8o 显示出比秋水仙碱（IC = 8.6 ± 0.2 µM）更高的微管聚合抑制活性（IC = 3.1 ± 0.5 µM），并通过破坏微管网络诱导细胞周期停滞在 G2/M 期和细胞凋亡。
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