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Research Article

2-苯基丙烯腈衍生物微管蛋白抑制剂的合成及选择性抗癌活性评价

卷 31, 期 15, 2024

发表于: 16 October, 2023

页: [2090 - 2106] 页: 17

弟呕挨: 10.2174/0109298673263854231009063053

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摘要

目的:合成13个系列的新型2-苯基丙烯腈衍生物，对其进行体内体外抗肿瘤活性评价，获得新型微管蛋白抑制剂。 方法:采用Knoevenagel缩合法合成13系2-苯基丙烯腈衍生物，采用MTT法测定其抗增殖活性。流式细胞仪检测细胞周期和凋亡情况。使用24孔Boyden室进行定量细胞迁移。Western blotting检测蛋白表达。采用人β-微管蛋白(Human β-tubulin, TUBB)酶联免疫吸附测定试剂盒测定微管组装的体外动力学。分子对接由Discovery Studio (DS) 2017客户端在线工具完成。 结果:化合物1g2a对HCT116细胞(IC50 = 5.9 nM)和BEL-7402细胞(IC50 = 7.8 nM)具有较强的抑制活性。化合物1g2a比包括紫杉醇在内的所有阳性对照药物具有更好的选择性抗增殖活性和特异性。化合物1g2a通过在细胞周期的G2/M期阻滞HCT116和BEL-7402细胞的增殖，抑制HCT116和BEL-7402细胞的迁移和细胞集落的形成。化合物1g2a对HCT116和BEL-7402细胞具有良好的微管蛋白聚合抑制活性。分子对接分析结果表明，1g2a可能抑制微管蛋白发挥抗癌作用。 结论:化合物1g2a在体内和体外均具有良好的抗肿瘤活性，具有进一步开发成为对正常组织毒性小的高效抗肿瘤药物的潜力。

关键词: 2-苯基丙烯腈，选择性毒性作用，细胞周期阻滞，细胞凋亡，异种移植模型，微管蛋白抑制剂。

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