有机化学 ›› 2020, Vol. 40 ›› Issue (2): 417-422.DOI: 10.6023/cjoc201907016 上一篇    下一篇

研究论文

含苯并噻唑砌块的2,4,6-三取代嘧啶衍生物的合成及抗肿瘤活性评价

李二冬a,d, 孟娅琪a,d, 张路野a,b, 张洋a,b, 周蕊a, 刘丽敏a, 栗娜b,c, 辛景超b,c, 郑甲信a,d, 单丽红a,b,c,d, 刘宏民a,b,c,d, 张秋荣a,b,c,d   

  1. a 郑州大学药学院 郑州 450001;
    b 新药创制与药物安全性评价河南省协同创新中心 郑州 450001;
    c 河南省药物质量评价重点实验室 郑州 450001;
    d 教育部药物制备关键技术重点实验室 郑州 450001
  • 收稿日期:2019-07-08 修回日期:2019-10-14 出版日期:2020-02-25 发布日期:2019-10-25
  • 通讯作者: 张秋荣, 刘宏民, 单丽红 E-mail:zqr409@yeah.net;liuhm@zzu.edu.cn;343785851@qq.com
  • 基金资助:
    国家自然科学基金(No.U1904163)和蛋白关键研究(No.2018YFE0195100)资助项目.

Synthesis and Antitumor Evaluation of 2,4,6-Trisubstituted Pyrimidine Derivatives Containing Benzothiazole Moiety

Li Erdonga,d, Meng Yaqia,d, Zhang Luyea,b, Zhang Yanga,b, Zhou Ruia, Liu Limina, Li Nabb,c, Xin Jingchaob,c, Zheng Jiaxina,d, Shan Lihonga,b,c,d, Liu Hongmina,b,c,d, Zhang Qiuronga,b,c,d   

  1. a School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001;
    b Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou 450001;
    c Key Laboratory of Henan Province for Drug Quality and Evaluation, Zhengzhou 450001;
    d Key Laboratory of Technology of Drug Preparation, Ministry of Education, Zhengzhou 450001
  • Received:2019-07-08 Revised:2019-10-14 Online:2020-02-25 Published:2019-10-25
  • Supported by:
    Project supported by the National Natural Science Foundation of China (No. U1904163) and the National Key Research Program of Proteins (No. 2018YFE0195100).

为了寻找高效的抗肿瘤药物,设计并合成了一系列含苯并噻唑砌块的2,4,6-三取代嘧啶衍生物.采用噻唑蓝(MTT)法对目标化合物在人类四种癌细胞[EC-109(人食管癌细胞)、MGC-803(人胃癌细胞)、PC-3(人前列腺癌细胞)、HepG-2(人肝癌细胞)]、GES-1(人正常胃黏膜上皮细胞)和HEEC(人正常食管细胞)中进行抗肿瘤活性评价,结果显示部分化合物对MGC-803和PC-3细胞表现出中度至强效的抗肿瘤活性.其中2-(((4-(4-(吡啶-2-基)哌嗪-1-基)-6-(三氟甲基)嘧啶-2-基)硫基)甲基)苯并[d]噻唑(13h)和2-(((4-(4-(嘧啶-2-基)哌嗪-1-基)-6-(三-氟甲基)嘧啶-2-基)硫代)甲基)苯并[d]噻唑(13i)对PC-3表现出比较好的抗肿瘤活性,IC50值分别3.82和2.29μmol/L,且化合物13h13i对GES-1的细胞增值毒性明显小于阳性对照5-氟尿嘧啶.

关键词: 嘧啶, 苯并噻唑, 合成, 抗肿瘤活性

In order to find high-efficiency antitumor drugs, a series of 2,4,6-trisubstituted pyrimidine derivatives containing benzothiazole moiety were designed, synthesized and evaluated for antitumor activities against four cancer cells (EC-109, human esophageal cancer cells; MGC-803, human gastric cancer cells; PC-3, human prostate cancer cells; HepG-2, human liver cancer cells), GES-1 (human normal gastric mucosal epithelial cells), and HEEC (human normal esophagus) using thiazolyl blue (MTT) method. The results showed that some compounds exhibited moderate to strong antitumor activities against MGC-803 and PC-3 cells. Among them, 2-(((4-(4-(pyridin-2-yl)piperazin-1-yl)-6-(trifluoromethyl)pyrimidin-2-yl)-thio)methyl)benzo[d]thiazole (13h) and 2-(((4-(4-(pyrimidin-2-yl)piperazin-1-yl)-6-(trifluoromethyl)pyrimidin-2-yl)thio)-methyl)benzo[d]thiazole (13i) showed the most potent antitumor activities against PC-3 cells with IC50 values of 3.82 and 2.29 μmol/L, respectively. The toxicities of compounds 13h and 13i to GES-1 cells were significantly lower than the positive control 5-fluorouracil.

Key words: pyrimidine, benzothiazole, synthesis, antitumor activity