Dideoxynucleosides as Potential Anti-AIDS Drugs

基于我们在碳环核苷（Z01 BC 006174）项目中关于“延迟链终止”机制的经验教训，今年我们实施了两条调查路线，以利用有效抗HIV活性所需的每个关键参数：(1)将4'-烷基（甲基和乙基）连接到2'-脱氧核糖片段；(2)在双环[3.1.0]己烷核苷的碳环部分结合双键，使其转化为扁平的双环[3.1.0]己-3-烯核苷。环平坦度被认为是细胞激酶有效磷酸化所必需的特性。重点介绍了这两个方面的进展：(1)成功合成了含4′-甲基和乙基的胸腺嘧啶系列。4'-甲基类似物在体外作为5'-三磷酸盐用于抗HIV-RT时表现出优异的延迟链终止物特性，但未能被细胞激酶识别。以腺嘌呤为核碱基的类似系列的合成正在进行中；(2)用含胸腺嘧啶的扁平双环[3.1.0]己-3-烯合成首个南方类似物

Based on the lessons learned from our project on carbocyclic nucleosides (Z01 BC 006174) regarding the mechanism of "delayed chain termination", two lines of investigation have been implemented this year to exploit each of the critical parameters necessary for efficient activity against HIV: (1) attachment of 4'-alkyl groups (methyl and ethyl) to a 2'-deoxyribose moiety; and (2) incorporation of a double bond onto the carbocyclic moiety of bicyclo[3.1.0]hexane nucleosides converting them into flat bicyclo[3.1.0]hex-3-ene nucleosides. Ring flatness is a property deemed essential for efficient phosphorylation by cellular kinases. Progress in these two areas is highlighted: (1) Synthesis of the thymidine series bearing 4'-methyl and ethyl groups was successfully completed. The 4'-methyl analogue showed excellent properties as a delayed chain terminator when used in vitro against HIV-RT as a 5'-triphosphate, but failed to be recognized by cellular kinases. The synthesis of an analogous series with adenine as nucleobase is in progress; and (2) The synthesis of the first South analogue with a flat bicyclo[3.1.0]hex-3-ene containing thymi