Dideoxynucleosides as Potential Anti-AIDS Drugs

根据我们从碳环核苷(Z01 BC 006174)项目中获得的关于“延迟链终止”机制的经验教训，今年实施了两项研究工作，以开发有效抗艾滋病毒活性所需的每一项关键参数：(1)将4‘-烷基(甲基和乙基)连接到2’-脱氧核糖部分；(2)在双环[3.1.0]己烷核苷的碳环部分上引入双键，将其转化为平面双环[3.1.0]六-3-烯核苷。环的平坦性被认为是被细胞激酶有效的磷酸化所必需的特性。重点介绍了这两个方面的进展：(1)合成了含4‘-甲基和乙基的胸腺嘧啶核苷系列化合物。4‘-甲基类似物在体外以5’-三磷酸的形式用于抗HIV-RT时，表现出良好的延迟链终止剂的性质，但不能被细胞激酶识别。以腺嘌呤为碱基的类似系列的合成正在进行中；以及(2)第一个南方类似物的合成，其中含有胸腺的平面型双环[3.1.0]六-3-烯

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