有机化学 ›› 2018, Vol. 38 ›› Issue (10): 2648-2656.DOI: 10.6023/cjoc201803041 上一篇    下一篇

研究论文

新型含2-氨基-4-苯基噻唑结构的c-Met抑制剂设计合成及抗肿瘤活性研究

张志华a, 陈羽b, 吴红梅a, 崔博c, 熊武林c, 林腾辉c, 林荣南c, 郭宇a   

  1. a 辽宁工业大学化学与环境工程学院 锦州 121001;
    b 沈阳药科大学生命科学与生物制药学院 沈阳 110016;
    c 锦州医科大学药学院 锦州 121001
  • 收稿日期:2018-03-25 修回日期:2018-06-06 发布日期:2018-06-15
  • 通讯作者: 郭宇,E-mail:guoyulnut@163.com E-mail:guoyulnut@163.com
  • 基金资助:

    国家自然科学青年基金(No.201601075)、辽宁省自然科学基金(No.2015020249)和辽宁省教育厅高校基本科研(No.JQL201715410)资助项目.

Design, Synthesis, and Biological Evaluation of Novel 2-Amino-4-phenylthiazole Derivatives as c-Met Inhibitors

Zhang Zhihuaa, Chen Yub, Wu Hongmeia, Cui Boc, Xiong Wulinc, Lin Tenghuic, Lin Rongnanc, Yu Guoa   

  1. a School of Chemical and Environmental Engineering, Liaoning University of Technology, Jinzhou 121001;
    b School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016;
    c College of Pharmacy, Jinzhou Medical University, Jinzhou 121001
  • Received:2018-03-25 Revised:2018-06-06 Published:2018-06-15
  • Contact: 10.6023/cjoc201803041 E-mail:guoyulnut@163.com
  • Supported by:

    Project supported by the National Natural Science Foundation for Young Scientists of China (No. 21601075), the Natural Science Foundation of Liaoning Province (No. 2015020249) and the General Research Projects of Liaoning Provincial Department of Education (No. JQL201715410).

基于克唑替尼的结构特征,设计、合成了两个系列未见文献报道的新型2-氨基-4-苯基噻唑类衍生物.采用噻唑蓝(MTT)法测试了目标化合物对A549、HT29、Hela、Karpas299的细胞增殖抑制活性.结果显示,部分化合物具有较好的肿瘤细胞抑制活性,其中N-(3-(2-氨基噻唑-4-基)苯基)-3-氯苯甲酰胺(3d)对HT29细胞的活性最好,IC50值为4.42 μmol/L.采用Western blot考察目标化合物3d在HT29细胞中MET信号通路中相关蛋白表达的影响.另外,利用分子对接方法,对目标化合物进行了初步的构效关系讨论.

关键词: 噻唑衍生物, c-Met抑制剂, 合成, 构效关系

Two series of novel 2-amino-4-phenylthiazole derivatives were designed and synthesized based on the structural features of crizotinib. The cell proliferation inhibition efficacy was estimated against A549, HT29, Hela and Karpas299 cell lines. The results revealed that some target compounds exhibited strong or moderate proliferation inhibition efficacy against tumor cells. N-(3-(2-Aminothiazol-4-yl)phenyl)-3-chlorobenzamide (3d) displayed significant activity against HT29 cancer cell with IC50 value of 4.42 μmol/L, and influence of this compound on the expression of related proteins in the MET signaling pathway in HT29 cells was investigated by Western blot. In addition, the preliminary structure-activity relationship (SAR) of the derivatives was rationalized by docking studies.

Key words: thiazole derivative, c-Met inhibitor, synthesis, structure-activity relationship