1,2-苯并噻嗪类化合物的设计、合成及抗肿瘤活性研究  

Design, Synthesis and Biological Activity of 1,2-Benzothiazine Derivatives as Potential Anticancer Agents

作　　者：王杰[1,2] 许勤龙[3] 李家明[1,2] 张恩立[1,2] 胡敏华[1,2] 叶文峰[1,2] 黄伟军[1,2] 

机构地区：[1]安徽中医药大学安徽省现代中药重点实验室,合肥230031 [2]安徽省中医药科学院药物化学研究所,合肥230038 [3]合肥医工医药有限公司,合肥230059

出　　处：《有机化学》2014年第10期2040-2046,共7页Chinese Journal of Organic Chemistry

基　　金：安徽省自然科学基金(No.1208085MH128);国家创新药物孵化基地(No.2012ZX09401066)资助项目~~

摘　　要：依据生物电子等排原理,设计合成了13个全新结构的1,2-苯并噻嗪类化合物,其结构均经IR,1H NMR,13C NMR和MS确证.以A431,A549,MDA-MB-468和HL60 4种细胞株为活性筛选对象,采用四甲基偶氮唑盐(MTT)法进行初步的体外抗肿瘤活性研究.结果表明,部分化合物对肿瘤细胞有一定的抑制活性,其中化合物5b对A431具有显著的抑制活性,IC50值为1.57μmol/L,化合物9a对A431,A549和MDA-MB-468 3种细胞株的抑制活性均强于阳性对照药gefitinib.并采用Moe软件对所合成的化合物与表皮生长因子受体(EGFR)结合位点进行对接,以进一步阐释所合成化合物的作用靶标.Thirteen 1,2-benzothiazine derivatives 5a^11a, 5b^10b have been designed and synthesized based on bioisosterism, and the structures of the target compounds were characterized by ^1H NMR, ^13C NMR, IR and mass spectra. The Anti-tumor activities of the target compounds against A549, A431, MDA-MB-468, HL60 cells in vitro were investigated by methyl thiazolyl tetrazolium （MTT） method. Most of the synthesized compounds were proved to have potent antitumor activity. Among them, compound 5b showed the most potent biological activity against A549 cell line with IC50 value of 1.57 μmol/L, compound 9a against A431, A549 and MDA-MB-468 had stronger cell growth inhibitory action than gefitinib. Molecular docking was performed to position compound 5b into epidermal growth factor receptor （EGFR） binding site in order to explore the potential target.

关 键 词：1 2-苯并噻嗪类化合物 酪氨酸激酶抑制剂 抗肿瘤 

分 类 号：O626[理学—有机化学]