新型2,4,6-三取代嘧啶衍生物的合成及抗增殖活性评价  

Synthesis and Antiproliferative Activity Evaluation of Novel 2,4,6-Trisubstituted Pyrimidine Derivatives

作　　者：高潮 张玉桐 池玲玲 王浩 马家婕 毕梦鑫 戴洪林 司晓杰 刘丽敏 张洋 郑甲信[1,2] 可钰 刘宏民[1,2,3,4] 张秋荣 Gao Chao;Zhang Yutong;Chi Lingling;Wang Hao;Ma Jiajie;Bi Mengxing;Dai Honglin;Si Xiaojie;Liu Limin;Zhang Yang;Zheng Jiaxin;Ke Yu;Liu Hongmin;Zhang Qiurong(School of Pharmaceutical Sciences,Zhengzhou University,Zhengzhou 450001;Collaborative Innovation Center of New Drug Research&Quality and Safety Evaluation,Zhengzhou 450001;State Key Laboratory of Esophageal Cancer Prevention&Treatment,Zhengzhou University,Zhengzhou 450052;Key Laboratory of Advanced Drug Preparation Technologies,Ministry of Education of China,Zhengzhou 450001)

机构地区：[1]郑州大学药学院,郑州450001 [2]新药创制与药物安全性评价河南省协同创新和药物质量与评价中心,郑州450001 [3]郑州大学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3824-3834,共11页Chinese Journal of Organic Chemistry

基　　金：国家自然科学基金(No.U21A20416);省部共建食管癌防治国家重点实验室开放基金(No.K2020000X)资助项目。

摘　　要：为了寻找新型高效的抗肿瘤药物,设计合成了一系列2,4,6-三取代嘧啶衍生物,并采用噻唑蓝(MTT)法测定目标化合物对PC-3(人前列腺癌细胞)、MGC-803(人胃癌细胞)、MCF-7(人乳腺癌细胞)、HGC-27(人未分化胃癌细胞)四种人肿瘤细胞的抗增殖活性.结果显示大部分化合物表现出中度至强效的抗增殖活性,其中N-(3-(2-((4-((1,3,4-噻二唑-2-基)硫代)-6-(三氟甲基)嘧啶-2-基)硫代)乙酰胺基)苯基)丙烯酰胺(19q)对PC-3细胞具有最好的抑制活性,IC50值为(0.87±0.15)μmol·L^(-1),抗肿瘤活性明显优于阳性对照5-氟尿嘧啶.进一步抗肿瘤机制研究表明,化合物19q可以诱导PC-3细胞凋亡.此外,化合物19q可能是通过下调抗凋亡蛋白Bcl-2的表达,上调促凋亡蛋白Bax和p53的表达而发挥抗肿瘤作用.In order to find new and efficient anti-tumor drugs,a series of 2,4,6-trisubstituted pyrimidine derivatives were designed and synthesized,and the antiproliferative activities were evaluated against four cancer cell lines of PC-3(human prostate cancer cells),MGC-803(human gastric cancer cells),MCF-7(human breast cancer cells)and HGC-27(human gastric carcinoma cell line)using methyl thiazolyl tetrazolium(MTT)assay.The results showed that most of the compounds exhibited moderate to potent antiproliferative activities against the four human tumor cell lines,among which N-(3-(2-((4-((1,3,4-thiadiazol-2-yl)thio)-6-(trifluoromethyl)pyrimidin-2-yl)thio)acetamido)phenyl)acrylamide(19q)had the best inhibitory activity against PC-3 cells with IC50value of(0.87±0.15)μmol·L^(-1),the antitumor activity was significantly better than the positive control 5-fluorouracil.Further anti-tumor mechanism studies showed that compound 19q could induce apoptosis in PC-3 cells.In addition,compound 19q might play an anti-tumor effect by down-regulating the expression of anti-apoptotic protein Bcl-2 and up-regulating the expression of pro-apoptotic proteins Bax and p53.

关 键 词：嘧啶衍生物 合成 抗增殖活性 

分 类 号：TQ463.5[化学工程—制药化工]