O5′,N6-双取代腺苷衍生物的合成及降血脂活性评价  

Synthesis and hypolipidemic activity of O^(5′),N^6-disubstituted adenosine derivatives

作　　者：郝玲花[1] 渠凯[1] 熊路[1] 魏金钊[1] 朱海波[1] 吴松[1] 

机构地区：[1]中国医学科学院北京协和医学院药物研究所,卫生部天然药物生物合成重点实验室,北京100050

出　　处：《中国药物化学杂志》2011年第1期7-11,共5页Chinese Journal of Medicinal Chemistry

基　　金：“重大新药创制”科技重大专项(2009ZX09301-003);中国医学科学院药物研究所基本科研业务费专项基金(2009CHX03)

摘　　要：目的设计合成O5′,N6-双取代腺苷衍生物,并评价其降血脂活性,寻找新型降血脂化合物。方法以6-氯嘌呤为起始原料,经4步反应合成目标化合物;通过测试目标化合物对油酸刺激下HepG2细胞内三酰甘油水平的影响及高胆固醇血脂症小鼠总胆固醇含量的影响评价化合物的活性。结果与结论合成了12个未见文献报道的新化合物,其结构经1H-NMR和MS谱确证。活性评价结果显示,多数化合物表现出良好的降血脂活性。Based on the good hypolipidemic activity of lead compound cordycepin,possible associated with mechanism of AMP-activated protein kinase,twelve novel compounds of adenosine derivatives,disubstituted with O5′-esterfunction and N6-substituted benzyl,were designed to replace the structure of deoxyribosyl in cordycepin with ribosyl and synthesized by four-step procedure including O2′,O3′-protection,esterification,deprotection and amination from 6-chloroadenosine.Moreover,the structure of these compounds were confirmed by 1H-NMR and MS.Hypolipidemic activity of ten selected compounds were detected in vitro by observing their effects on triglyceride content in HepG2 cells with oleic acid stimulation.Compounds 1c,1f,1h,1i,1k,and 1l showed good activities at 1 μmol · L-1 concentration,and the most potent compound 1k was identified as potent novel hypolipidemic compound with its comparable activity to simvastatin.In addition,by determining content of total cholesterol in hypercholesterolemic mice,1b,1c and 1d among six tested compounds exhibited the efficacy on reducing total cholesterol content at 50 mg · kg-1 dose.

关 键 词：合成 腺苷衍生物 降血脂活性 

分 类 号：R914[医药卫生—药物化学]