6-取代氨基-L-D4G/ddG-5'-单磷酸酯的合成与抗HIV活性研究  

Synthesis and anti-HIV activity of 6-modified L-D4G/ddG-5'-monophosphates

作　　者：蒙卓明 杨先桃[1] 郭颖[2] 关注[1] 张礼和[1] 杨振军[1] 

机构地区：[1]北京大学药学院天然药物及仿生药物国家重点实验室,北京100191 [2]中国协和医科大学中国医学科学院药物研究所,北京100050

出　　处：《中国药物化学杂志》2015年第2期93-99,共7页Chinese Journal of Medicinal Chemistry

基　　金：国家自然科学基金项目(21172010;21332010)

摘　　要：目的前期工作发现一些碱基6位胺取代2',3'-双脱氧-2',3'-双脱氢鸟苷(D4G)和2',3'-双脱氧鸟苷(dd G)在体外实验中表现出良好的抗HIV活性,而碱基6位胺取代的L-D4G/dd G却无活性。推测其活性缺失可能与代谢过程中单磷酸化限速步骤有关。鉴于此,作者设计合成了L-D4G/dd G-5'-单磷酸酯,并对其抗HIV活性进行评价。方法本文以L-四乙酰核糖和6-氯-鸟嘌呤为原料,按已有合成方法合成中间体L-6-氯-2',3'-双脱氧-2',3'-双脱氢鸟苷,然后经磷酸酯化、胺取代、催化氢化等反应合成目标化合物。在假病毒评价体系中,以依法韦仑为阳性对照,对目标化合物进行抗HIV活性评价。结果合成了6个L-D4G/dd G-5'-单磷酸酯,抗HIV体外活性评价结果表明,与没有抗病毒活性的前体结构相比,化合物3a、3c、4a、4c的病毒抑制率有所提高。结论作为潜在的核苷抗病毒药物,L-D4G/dd G单磷酸酯前药的结构优化具有进一步深入研究的意义。In previous work some 6-modified D4G/ddG analogues displayed benign anti-HIV activities while their L-isomers did not. The inactivation of L-D4G/ddG analogues might be related to their monophosphorylation, the rate-limiting step during the bioconversion of nucleoside analogues to their active triphosphates. In order to bypass monophosphoration in vivo, starting from tetra-O-acetyl-L-ribose and 6-chloro-guanine, intermediate L-6-choloro-D4G was synthesized by published method, then via monophosphorylation, amine substitution and catalytic hydrogenation, six new 6-alkylamino-L-D4G/ 6-alkylamino-ddG-5＇-monophosphate esters were synthesized. Anti-viral activities evaluation was performed in pseudotyped virus system using Efavirenz as positive control. Compounds 3a ,3e ,4a and 4c displayed higher activity than their precursos la, le,2a and 2e. Though some key steps in the metabolism of 6-modified L-D4G/ddG and their monophosphate esters still need to be revealed, as potential novel anti-viral agents, derivatives of L-D4G/ddG should be further investigated.

关 键 词：L-2' 3'-双脱氧-2' 3'-双脱氢鸟苷 L-2' 3'-双脱氧鸟苷 单磷酸酯 抗HIV活性 

分 类 号：R914.5[医药卫生—药物化学] R96[医药卫生—药学]