2-取代-9-苄基嘌呤-6-酮衍生物的合成、磷酸二酯酶-2抑制活性以及分子对接研究(英文)  

Synthesis of 9-benzyl-2-substituted-purin-6-one derivatives and their bioactivity and molecular docking as potential human phosphodiesterase-2 inhibitors

作　　者：赵新筠[1,3] 陈喜[1,3] 杨光富 湛昌国[3] 

机构地区：[1]中南民族大学化学与材料科学学院,湖北武汉430074 [2]华中师范大学化学学院,湖北武汉430079 [3]美国肯塔基大学药学院,肯塔基州40536

出　　处：《中国药物化学杂志》2013年第4期277-285,共9页Chinese Journal of Medicinal Chemistry

基　　金：supported by the Special Fund for Basic Scientific Research of Central Colleges,South-Central University for Nationalities(CZY11004);in part by the National Institutes of Health(RC1MH088480);Natural Science Foundation(CHE-1111761);National Natural Science Foundation of China(20602014,20503008,20372023,21273089)

摘　　要：目的设计和合成了6个2-取代-9-苄基-嘌呤-6-酮衍生物并测试了其对磷酸二酯酶-2的抑制活性,进而研究PDE2酶对该类抑制剂的作用方式。方法以2-氨基-2-氰基乙酰胺为原料先合成5-氨基-4-羰酰胺咪唑类衍生物,接着用微波辅助的方法合成了目标化合物。结果与结论微波辅助的方法大大缩短反应时间,从传统的加热回流20 h缩短到目前的30 min。抑制活性结果表明,化合物2b[9-苄基-2-(3,4-二甲氧基苄基)-1,9-二氢嘌呤-6-酮]有非常明显的抑制活性(IC50=1.35μmol.L-1)。配体和蛋白质对接的结果分析表明,嘌呤-6-酮衍生物同磷酸二酯酶-2的催化区域的结合主要通过氢键和π-π堆积作用实现的。A novel approach to synthesize six purin-6-one derivatives in microwave hradiation conditions was reported in this study. The reaction time was dramatically reduced to 30 rain. Inhibitory activity tests against phosphodiesterase-2 （ PDE2 ） show that compound 2b （ 9-benzyl-2- （3,4-dimethoxy-benzyl） -1,9-dihydro-pu- rin-6-one） exhibits a significant inhibitory effect with an IC50 value of 1.35 μmol. L-1. The results from lig- and-protein docking and analysis reveal that these purin-6-one derivatives interact with the PDE2 catalytic domain via hydrogen bonding and π-π stacking interactions.

关 键 词：合成 嘌呤-6-酮衍生物 磷酸二酯酶-2抑制活性 分子对接 

分 类 号：R914[医药卫生—药物化学]