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

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.