新型拟天然芪类拓扑异构酶Ⅰ抑制剂的设计与合成  

Design and Synthesis of Novel Nature-Inspired Stilbene Analogues as Potential Topoisomerase 1 Inhibitors

作　　者：陆棋 叶飞霞 孙晓彤 翁建全[1] 余茜 胡德玄 Lu Qi;Ye Feixia;Sun Xiaotong;Weng Jianquan;Yu Qian;Hu Dexuan(College of Chemical Engineering,Zhejiang University of Technology,Hangzhou 310014;School of Clinical Pharmacy,Guangdong Pharmaceutical University,Guangzhou 510006;School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006)

机构地区：[1]浙江工业大学化学工程学院,杭州310014 [2]广东药科大学临床药学院,广州510006 [3]中山大学药学院,广州510006

出　　处：《有机化学》2021年第8期3321-3329,共9页Chinese Journal of Organic Chemistry

基　　金：浙江省自然科学基金(No.LY17C140003)资助项目.

摘　　要：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.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(6 k) 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(6 e),(E)-5-bromo-2-(2-chlorostyryl)-4-(4-fluorophenyl)thiazole(6 k), and(E)-5-bromo-2-(4-chlorostyryl)-4-(4-fluorophenyl)thiazole(6 l) showed high cytotoxicity at low micromolar concentrations.

关 键 词：天然芪 噻唑 拓扑异构酶Ⅰ抑制剂 合成 细胞毒性 

分 类 号：TQ460.1[化学工程—制药化工]