7-硝基吲哚酰基芳磺酰胺类FBPase抑制剂的设计合成、活性评价及结合模式分析  

Design,synthesis,biological evaluation and binding mode analysis of 7-nitro-indole-N-acylarylsulfonamide- based fructose-1,6-bisphosphatase inhibitors

作　　者：别建波 王晓宇 刘率男[2] 周洁 刘泉[2] 申竹芳[2] 徐柏玲 BIE Jian-bo;WANG Xiao-yu;LIU Shuai-nan;ZHOU Jie;LIU Quan;SHEN Zhu-fang;XU Bai-ling(Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation,Institute of Materia Medica,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China;Department of pharmacology,Institute of Materia Medica,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China)

机构地区：[1]中国医学科学院/北京协和医学院药物研究所活性物质发现与适药化研究北京市重点实验室,北京100050 [2]中国医学科学院/北京协和医学院药物研究所药理学系,北京100050

出　　处：《中国药物化学杂志》2020年第12期713-724,共12页Chinese Journal of Medicinal Chemistry

基　　金：国家自然科学基金项目(81502933,81973379);北京市自然科学基金项目(7132138,7202137)

摘　　要：目的设计合成新结构果糖-1,6-二磷酸酶(FBPase)抑制剂,评价其对FBPase的抑制活性,探索构效关系及结合模式。方法利用生物电子等排体策略,设计新结构的7-硝基-吲哚酰基芳磺酰胺类化合物。以取代的7-硝基-吲哚-2-羧酸类化合物为关键中间体,与取代的磺酰胺发生缩合反应得到目标化合物。采用磷酸葡萄糖异构酶(PGIase)和葡萄糖-6-磷酸脱氢酶(G-6-PDH)偶联实验,评价化合物对FBPase的抑制作用。采用结构生物学方法,培养解析目标化合物与FBPase复合物的晶体结构。结果设计合成了18个未见文献报道的7-硝基-吲哚酰基芳磺酰胺类衍生物(21~38),目标化合物结构经1H-NMR、LC-MS谱确证,部分化合物结构经13C-NMR进一步确证。发现10个化合物对FBPase具有抑制活性(IC50值为0.15~5.80μmol·L-1),4-芳基-吲哚酰基芳磺酰胺类化合物(32~34)抑制活性显著(IC50值为0.15~0.21μmol·L-1)。解析了化合物34与FBPase复合物的晶体结构,揭示了该类化合物的结合模式。结论4-芳基吲哚酰基芳磺酰胺类化合物是新结构类型的FBPase抑制剂,该类化合物独特的结合模式为获得高活性和类药性FBPase抑制剂提供了结构基础。Excessive endogenous glucose production through elevated gluconeogenesis(GNG)is positively correlated with high blood glucose levels of type 2 diabetes patients.As a key enzyme in the GNG pathway,fructose-1,6-bisphosphatase(FBPase)catalyzes the conversion of fructose-1,6-bisphosphate to fructose-6-phosphate.Therefore,the inhibition of FBPase activity represents a potential new approach for the treatment of type 2 diabetes.In this work,a series of novel 7-nitro-indole-N-acylarylsulfonamide derivatives were designed and synthesized,and their inhibitory activities against FBPase were evaluated.The structure-activity relationships demonstrated that 4-aryl-indole-N-acylarylsulfomamide derivatives could produce potent FBPase inhibition,and three compounds(32-34)were found to strongly inhibit FBPase with IC50 values of 0.15~0.21μmol·L-1.The X-ray co-crystal structure of compound 34 bound to FBPase revealed that this class of inhibitors displayed a distinct binding mode,which provided a structural basis for further developing highly potent and drug-like FBPase inhibitors.

关 键 词：FBPASE 抑制剂 吲哚酰基芳磺酰胺 抗糖尿病药物 

分 类 号：R914.5[医药卫生—药物化学]