三七素类似物的合成及促凝活性研究  

Research on Synthesis and Procoagulant Activity of Dencichine Analogues

作　　者：张曦 赵梦诗 陈紫怡 陈靓 张然然 秦文亮 李军 孙敬勇 ZHANG Xi;ZHAO Meng-shi;CHEN Zi-yi;CHEN Liang;ZHANG Ran-ran;QIN Wen-liang;LI Jun;SUN Jing-yong(School of Pharmaceutical Sciences&Institute of Materia Medica,Shandong First Medical University&Shandong Academy of Medical Sciences,Jinan 250117,China)

机构地区：[1]山东第一医科大学药学院(药物研究所),山东济南250117

出　　处：《食品与药品》2024年第2期116-121,共6页Food and Drug

基　　金：国家中医药管理局科技司-山东省卫生健康委员会共建中医药科技项目(编号:GZY-KJS-SD-2023-086)。

摘　　要：目的 研究在三七素分子上以显酸性的四氮唑基团进行电子等排替换对其促凝活性的影响。方法 以N2-Fmoc-L-2, 3-二氨基丙氨酸为原料,分别与2H-1, 2, 3-三氮唑-2-乙酸,1H-1, 2, 4-三氮唑-1-乙酸,1H-四氮唑-5-乙酸反应,合成3种三七素类似物,并通过质谱(MS)、核磁共振氢谱(1H NMR)及核磁共振碳谱(13C NMR)对其结构进行确证。结果 3种三七类似物分别为2-({[(9H-芴-9-基甲基)氧基]羰基}氨基)-3-{[2-(1, 2, 3-三氮唑-2-基)乙酰基]氨基}丙酸(Ⅰ),2-({[(9H-芴-9-基甲基)氧基]羰基}氨基)-3-{[2-(1, 2, 4-三氮唑-1-基)乙酰基]氨基}丙酸(Ⅱ)及2-({[(9H-芴-9-基甲基)氧基]羰基}氨基)-3-{[2-(3H-1, 2, 3, 4-四氮唑-5-基)乙酰基]氨基}丙酸(Ⅲ)。凝血4项检查与血浆复钙时间检测表明,Ⅲ的促凝血活性优于Ⅰ、Ⅱ。结论 在三七素分子上以显酸性的四氮唑基团进行电子等排替换,对其促凝活性有一定的增强作用。Objective To study the effect of electronic isosteric substitution with acidic tetrazolium groups on the coagulation promoting activity of dencichine.Methods Three analogues of dencichine were synthesized by reacting N2-Fmoc-L-2,3-diaminoalanine with 2H-1,2,3-triazole-2-acetic acid,1H-1,2,4-triazol-1-acetic acid,1H-tetrazol5-acetic acid,respectively.The structures of the resulting compounds were confirmed by 1 H NMR,13C NMR and MS.Results Three analogues,including 3-(2-(2H-1,2,3-triazol-2-yl)acetamido)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanoic acid(I),3-(2-(1H-1,2,4-triazol-1-yl)acetamido)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanoic acid(II)and 3-(2-(2H-tetrazol-5-yl)acetamido)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanoic acid(III)were obtained.Four items of blood coagulation tests(APTT,PT,TT and FIB)and plasma recalcification time test indicated that derivative III had better procoagulant properties than I and II.Conclusion Electron isosteric substitution with acidic tetrazolium groups on dencichine molecule has a certain enhancing effect on its procoagulant activity.

关 键 词：三七素 类似物 凝血4项 血浆复钙时间 促凝活性 

分 类 号：R914.2[医药卫生—药物化学]