摘要/Abstract
为了寻找新型抗肿瘤药物先导, 设计合成了23个含噻唑环的天然芪类似物, 其结构均经NMR和ESI-HRMS表征确证. 通过Top1-介导的松散实验筛选了目标化合物的拓扑异构酶I (Top1)抑制活性, 其中(E)-5-溴-2-(2-氯苯乙烯基)-4-对氟苯基噻唑(6k)显示出了良好的Top1抑制活性. 同时通过分子对接研究其构效关系, 结果表明化合物的Top1抑制活性与分子对接研究之间具有良好的相关性. 此外, 采用3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐(MTT)法测定了化合物对人乳腺癌细胞(MCF-7)和人结肠癌细胞(HCT116)的体外抗肿瘤活性, 结果表明(E)-5-溴-4-对氟苯基- 2-(4-三氟甲基苯乙烯基)噻唑(6e)、(E)-5-溴-2-(2-氯苯乙烯基)-4-对氟苯基噻唑(6k)和(E)-5-溴-2-(4-氯苯乙烯基)-4-对氟苯基噻唑(6l)在低摩尔浓度下表现出较高的细胞毒活性.
关键词: 天然芪, 噻唑, 拓扑异构酶I抑制剂, 合成, 细胞毒性
In order to find novel antitumor drug leads, twenty-three nature-inspired stilbene analogues containing thiazole moiety were designed and synthesized, and their structures were confirmed by NMR and ESI-HRMS. These compounds were screened for their topoisomerase I (Top1) inhibitory activity using Top1-mediated relaxation assay, and (E)-5-bromo-2- (2-chlorostyryl)-4-(4-fluorophenyl)thiazole (6k) possessed promising Top1 inhibitory activity. Molecular docking was also established to study the structure-activity relationship and a good correlation was observed between Top1 inhibitory activity and molecular docking study. Furthermore, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay against human breast cancer (MCF-7) and human colon cancer (HCT116) cell lines indicated that (E)-5-bromo-4-(4-fluorophenyl)- 2-(4-(trifluoromethyl)styryl)thiazole (6e), (E)-5-bromo-2-(2-chlorostyryl)-4-(4-fluorophenyl)thiazole (6k), and (E)-5-bromo- 2-(4-chlorostyryl)-4-(4-fluorophenyl)thiazole (6l) showed high cytotoxicity at low micromolar concentrations.
Key words: natural stilbene, thiazole, topoisomerase 1 inhibitor, synthesis, cytotoxicity
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