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  

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

作　　者：董潜[1] 彭霞 王雯[1] 戴阳 赵伟利[1] 艾菁 董肖椿[1] 

机构地区：[1]复旦大学药学院,上海201203 [2]中国科学院上海药物研究所肿瘤药理室,上海201203

出　　处：《有机化学》2015年第9期1939-1947,共9页Chinese Journal of Organic Chemistry

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

摘　　要：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8和18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.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·L^-1, 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·L^-1, respectively.

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 

分 类 号：O626[理学—有机化学] TQ460.1[理学—化学]