DIDEOXYNUCLEOSIDES AS POTENTIAL ANTI-AIDS DRUGS

所有单氟取代的和 具有尿嘧啶的二氟取代的二脱氧呋喃戊糖基核苷，和 胞嘧啶碱基是通过使用可变的 温度/高场1H NMR研究。 有史以来第一次合成 具有β-D-lyxo构型的双脱氧二氟核苷， 完成了 β-D-lyxo立体化学与 前所未有的反应性的苷元部分，允许转换 通过简单处理将尿嘧啶类似物转化为相应的胞嘧啶 与氨水在室温下反应。 通常，这种转换 需要尿嘧啶部分的两步活化。 一项类似的研究 与相应的4 '-硫代二脱氧呋喃戊糖基核苷反应， 完成到所有的X射线结构都已经完成的阶段 安全 变温/高场1H NMR研究继续进行， 为该系列建立了一种新的构象活性关系， 似乎与二脱氧呋喃戊糖基系列显著不同。 设计并合成了具有活性的F-ddI前药， 以改善抗HIV ddN转运到CNS中的性质。 发现羟基脲可增强双脱氧嘌呤的活性 核苷ddI和F-ddA。 LMC抗艾滋病化合物F-ddA计划开始临床试验 在1995年。

A conformation-activity relationship for all monofluoro-substituted and difluoro-substituted dideoxypentofuranosyl nucleosides with uracil and cytosine bases was established through the use of variable temperature/high field 1H NMR studies. The first synthesis ever of a dideoxydifluoro nucleoside with a beta-D-lyxo configuration was accomplished. The beta-D-lyxo stereochemistry was associated with an unprecedented reactivity of the aglycon moiety that permitted conversion of the uracil analogue to the corresponding cytosine by simple treatment with aqueous ammonia at room temperature. Normally, this conversion requires a two-step activation of the uracil moiety. A similar study with the corresponding 4'-thiodideoxypentofuranosyl nucleosides was completed to the stage that all of the X-ray structures have been secured. Variable temperature/high field 1H NMR studies continue to establish a new conformation-activity relationship for this series that appears to differ significantly from the dideoxypentofuranosyl series. Active F-ddI prodrugs have been designed and synthesized in an attempt to improve anti-HIV ddN transport properties into the CNS. Hydroxyurea was found to potentiate the activity of the dideoxypurine nucleosides ddI and F-ddA. F-ddA, an LMC anti-AIDS compound, is scheduled to start clinical trials during 1995.