9-取代-2-氨基-6-胍基嘌呤类精子顶体酶抑制剂的设计、合成及活性评价  

Design,Synthesis and Activity Evaluation of 9-Substituted-2-amino-6-guanidinopurines as Acrosin Inhibitors

作　　者：张晓梦[1] 朱驹[1] 刘雪飞[1] 盛春泉[1] 郑灿辉[1] 付小旦[1] 宋云龙[1] 周有骏[1] 吕加国[1] 

机构地区：[1]第二军医大学药学院药物化学教研室,上海200433

出　　处：《高等学校化学学报》2010年第9期1753-1761,共9页Chemical Journal of Chinese Universities

基　　金：上海市计划生育委员会科研基金(批准号:2007JG02);上海市重点学科建设项目基金(批准号:B906)资助

摘　　要：顶体酶是存在于精子顶体内的一种胰蛋白酶样的丝氨酸水解酶,是目前男性抗生育药物设计的潜在靶点之一.在前期对精子顶体酶同源模建的基础上,根据活性腔结构和活性位点性质,以KF950为先导化合物,设计合成了一类胍基鸟嘌呤化合物,采用核磁共振氢谱、质谱、红外光谱和元素分析等手段对其结构进行了表征,其中中间体5m的结构经X射线单晶衍射分析确证.以N-甲苯磺酰-L-赖氨酸-氯甲基酮(TLCK)为阳性对照,分别测定了目标化合物对精子顶体酶的体外抑制活性.结果表明,化合物6a～6z的酶抑制活性均强于TLCK,其中化合物6z抑制活性与KF950相当.Acrosin,a trypsin-like endoprotease,present in the acrosome of spermatozoa,is a promising target for contraceptive agents. Based on the previous homology modeling and the analysis of the properties of the activity site of human acrosin,a series of 9-substituted-2-amino-6-guanidinopurines were designed and synthesized on a scaffold represented by KF950. The structrues of all the title compounds were comfirmed by 1 H NMR,MS,IR and elemental analysis. Intermediate 5m was determined by single crystal X-ray diffraction analysis. The inhibitory activities against acrosin of all target compounds were tested in vitro and all of them exhibited much more inhibitory activities against acrosin,respectively,with positive control,TLCK. Compound 6z exhibited similar inhibitory activities against KF950. The activity results indicate the following structure-activity relationship（ SAR） ： （ 1） the introduction of disubstituded groups at aryl moiety caused better inhibitory activities than those of monosubstituded groups; （ 2） lower inhibitory activities were also observed for the compounds bearing electron-donating groups（ 6q—6w） comparing with the compounds bearing withdrawing electron groups（ 6b—6p） ; （ 3） long chain substituents at 9-position（ 6x—6z） can enhance the inhibitory activity signficantly.

关 键 词：顶体酶抑制剂 活性腔 胍基鸟嘌呤 晶体结构 抑制活性 

分 类 号：O629[理学—有机化学]