有机化学 ›› 2015, Vol. 35 ›› Issue (9): 1939-1947.DOI: 10.6023/cjoc201503045 上一篇    下一篇

研究论文

5-氨基吡唑及5-氨基三唑类成纤维细胞生长因子受体激酶抑制剂的设计合成

董潜a, 彭霞b, 王雯a, 戴阳b, 赵伟利a, 艾菁b, 董肖椿a   

  1. a 复旦大学药学院 上海 201203;
    b 中国科学院上海药物研究所 肿瘤药理室 上海 201203
  • 收稿日期:2015-03-27 修回日期:2015-04-30 出版日期:2015-09-25 发布日期:2015-05-15
  • 通讯作者: 艾菁, 董肖椿 E-mail:jai@simm.ac.cn;xcdong@fudan.edu.cn
  • 基金资助:

    教育部博士点基金(No. 20130071110071)和上海市科技支撑计划(No. 13431900102)资助项目.

Design and Synthesis of 5-Aminopyrazole and 5-Aminotriazole Derivatives as Fibroblast Growth Factor Receptor Inhibitors

Dong Qiana, Peng Xiab, Wang Wena, Dai Yangb, Zhao Weilia, Ai Jingb, Dong Xiaochuna   

  1. a School of Pharmacy, Fudan University, Shanghai 201203;
    b Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai 201203
  • Received:2015-03-27 Revised:2015-04-30 Online:2015-09-25 Published:2015-05-15
  • Supported by:

    Project supported by the Specialized Research Fund for the Doctoral Program of Higher Education of China (No. 20130071110071) and the Shanghai Municipal Science & Technology Pillar Program for Bio-pharmaceuticals (No. 13431900102).

成纤维细胞生长因子受体(FGFR)是近年来抗肿瘤靶向治疗药物研发的前沿热点. 本研究以Debio1347为先导化合物, 依据其与FGFR蛋白的对接结果, 设计并合成了11个5-氨基吡唑及5-氨基-1,2,3-三唑类FGFR抑制剂. 测定了化合物对受体酪氨酸激酶FGFR2以及FGFR2依赖型胃癌细胞株(SNU16)的体外抑制活性, 并对其构效关系进了初步的探讨. 其中, 1-[5-氨基-1-(2-甲基-1H-苯并[d]咪唑-6-基)-1H-吡唑-4-基]-1-(1H-噻吩并[3,2-b]吡咯-2-基)甲酮(8)与1-[5-氨基-1-(2-甲基-1H-苯并[d]咪唑-6-基)-1H-1,2,3-三唑-4-基]-1-(1H-吲哚-2-基)甲酮(18)在酶水平上表现出了与Debio1347 (3.5 nmol·L-1)相近的活性, 其IC50值分别为3.3, 2.3 nmol·L-1; 在细胞水平上, 化合物818与Debio1347 (37.7 nmol· L-1)相比较活性略微降低, 其IC50值分别为77.3, 155.2 nmol·L-1.

关键词: 5-氨基吡唑, 5-氨基-1,2,3-三唑, FGFR抑制剂, 抗肿瘤药物

Fibroblast growth factor receptor (FGFR) is a promising therapeutic target for cancer treatment. A series of 5-aminopyrazole and 5-amino-1,2,3-triazole derivatives were designed as FGFR inhibitors based on the docking mode of Debio1347 within the FGFR kinase domain. The inhibitory effects on FGFR2 kinase and the antitumor activities against human gastric cancer SNU16 cell lines were evaluated. Furthermore, the preliminary structure-activity relationships (SAR) was discussed. The results demonstrated that several compounds present good potency against FGFR2 kinase. 1-(5-Amino-1-(2-methyl-1H-benzo[d]imidazol-6-yl)-1H-pyrazol-4-yl)-1-(1H-thieno[3,2-b]pyrrol-2-yl)methanone (8) and 1-(5-amino-1-(2-methyl-1H-benzo[d]imidazol-6-yl)-1H-1,2,3-triazol-4-yl)-1-(1H-indol-2-yl)methanone (18) were the most potent with IC50 values of 3.3 and 2.3 nmol·L1, respectively, which are similar to that of Debio1347. Compounds 8 and 18 exhibited slightly weaker antitumor activity against SNU16 cell lines than Debio1347 with IC50 value of 77.3, 155.2 nmol·L1, respectively.

Key words: 5-aminopyrazole, 5-amino-1,2,3-triazole, FGFR inhibitors, anti-tumor agent