吡嗪类化合物的合成及其抗血小板凝集活性测试  

Syntheses and Anti-Platelet Aggregations Activity Evaluations of Pyrazines

作　　者：樊玲玲 李毅 罗碧兰 范菊娣 李永 汤磊 Fan Lingling;Li Yi;Luo Bilan;Fan Judi;Li yong;Tang Lei(College of Pharmacy,Guizhou Medical University,Guiyang 550025)

机构地区：[1]贵州医科大学药学院,贵阳550025

出　　处：《化学通报》2019年第2期128-132,97,共6页Chemistry

基　　金：贵州省化学合成药物研发利用工程技术研究中心项目(黔科合[2016]平台人才5402);贵州省普通高等学校药物化学工程研究中心项目(黔教合KY字[2014]219号);贵州省卫生计生委科学技术基金项目(gzwjkj2016-1-050);贵州省科技计划项目(黔科合支撑[2017]2835;黔科合重大专项字[2014]6008);贵阳市科技局联合基金[筑科合同[2017]30-28]资助

摘　　要：为提高川芎嗪的抗血小板凝集活性,分别以不同的二胺、2,3-丁二酮和硫辛酸为起始原料,采用溴代、水解、环化、氧化、氢化、取代等反应,通过四条路线合成了7个川芎嗪衍生物,其结构经1H NMR、13C NMR及ESI-MS确证。采用Born比浊法初步测试了化合物的体外抗血小板凝集活性,结果显示,化合物1(IC50=0. 26mmol/L)、2(IC50=0. 27mmol/L)和7(IC50=0. 21mmol/L)对由二磷酸腺苷(ADP)诱导的血小板凝集具有一定的抑制活性,优于先导化合物川芎嗪(IC50=0. 49mmol/L)。因此,在不改变川芎嗪药效团的前提下对其进行不同程度的环化,能明显提高川芎嗪的抗血小板凝集活性,此研究为后期化合物的结构修饰提供了一定的参考价值。In order to improve the antiplatelet agglutination activity of ligustrazine,different diamines,2,3-butanedione and lipoic acid were used as starting materials,seven ligustrazine derivatives were synthesized via four routes,including bromination,hydrolysis,cyclization,oxidation,hydrogenation and substitution reaction. Their structures were confirmed by ^1H NMR,^13C NMR and ESI-MS,and the in vitro anti-platelet aggregation activities were tested preliminarily by the Born turbidimetric method. The experimental results showed that compounds 1( IC50=0. 26 mmol/L),2( IC50= 0. 27 mmol/L) and 7( IC50= 0. 21 mmol/L) exhibit significant inhibitory activity for adenosine diphosphate( ADP) induced platelet aggregation,which are superior to the lead compound ligustrazine( IC50= 0. 49 mmol/L). Therefore,without changing ligustrazine pharmacophore,cyclization in different degree can obviously improve the antiplatelet agglutination activity of ligustrazine,which has useful reference value for the structure modification of lead compound.

关 键 词：川芎嗪衍生物 设计 合成 抗血小板凝集活性 

分 类 号：TQ460.1[化学工程—制药化工]