含噻唑结构的2,4,6-三取代喹唑啉衍生物的合成及抗肿瘤活性研究  

Synthesis and Antitumor Activity Evaluation of 2,4,6-Trisubstituted Quinazoline Derivatives Containing Thiazole Structure

作　　者：戴洪林 司晓杰 池玲玲 王浩 高潮 汪正捷 刘丽敏 马家婕 于富强 刘宏民[1,2,3,4] 可钰 张秋荣[1,2,3,4] Dai Honglin;Si Xiaojie;Chi Lingling;Wang Hao;Gao Chao;Wang Zhengjie;Liu Limin;Ma Jiajie;Yu Fuqiang;Liu Hongmin;Ke Yu;Zhang Qiurong(School of Pharmaceutical Sciences,Zhengzhou University,Zhengzhou 450001;Collaborative Innovation Center of New Drug Research and Safety Evaluation,Zhengzhou 450001;Key Laboratory of Advanced Drug Preparation Technologies,Ministry of Education,Zhengzhou 450001;State Key Laboratory of Esophageal Cancer Prevention&Treatment,Zhengzhou 450052)

机构地区：[1]郑州大学药学院,郑州450012 [2]新药创制与药物安全性评价河南省协同创新中心,郑州450001 [3]省部共建食管癌防治国家重点实验室,郑州450052 [4]教育部药物制备关键技术重点实验室,郑州450001

出　　处：《有机化学》2022年第11期3853-3862,共10页Chinese Journal of Organic Chemistry

基　　金：国家自然科学基金(No.U1904163)资助项目。

摘　　要：设计合成了一系列含有噻唑结构的2,4,6-三取代喹唑啉衍生物,并测定了他们对PC-3(人前列腺癌细胞系)、H1975(人肺腺癌细胞系)、MGC-803(人胃癌细胞系)和A549(人非小细胞肺癌细胞系)四种人肿瘤细胞的抗增殖活性.其中,3-((2-(((2-氯噻唑-5-基)甲基)硫代)-6-甲氧基喹唑啉-4-基)氨基)苯甲氰(14i)是抗MGC-803细胞增殖活性最好的化合物,IC_(50)为(4.54±0.32)μmol/L,优于阳性对照5-氟尿嘧啶(5-FU)[(8.14±0.68)μmol/L],其作用机理实验显示化合物14i具有抑制MGC-803细胞克隆增殖和迁移,以及可诱导细胞凋亡的作用,并且可以将MGC-803细胞周期阻滞在DNA合成后期/有丝分裂期(G2/M).这些结果表明,化合物14i可作为一种潜在的抗肿瘤药物.A series of 2,4,6-trisubstituted quinazoline derivatives containing thiazole group were designed and synthesized,and their antiproliferative activities against human tumor cell lines(PC-3,H1975,MGC-803 and A549)were determined.3-((2-(((2-chlorothiazol-5-yl)methyl)thio)-6-methoxyquinazolin-4-yl)amino)benzonitrile(14i)was identified as the most potent compound in antiproliferation against MGC-803 cells,with the value was(4.54±0.32)μmol/L,which was better than the positive control 5-fluorouracil(5-FU)[(8.14±0.68)μmol/L].Further mechanistic studies showed that compound 14i could inhibit the clonal proliferation and migration of MGC-803 cells.In addition,compound 14i could induce apoptosis of MGC-803 cells and arrest the cell cycle at late period of DNA synthesis/mitotic phase(G2/M)phase.These results indicated that compound 14i could as a potential antitumor drug.

关 键 词：噻唑 喹唑啉 抗肿瘤活性 合成 

分 类 号：O626[理学—有机化学] TQ460.1[理学—化学]