Dideoxynucleosides as Potential Anti-AIDS Drugs

该项目的主要重点是开发具有能够克服艾滋病毒耐药性的新作用机制的核苷类似物。目前的重点包括两大类结构：1）4 '-烷基-2'-脱氧核苷。合成这些化合物的目的是实现HIV逆转录酶催化的病毒DNA合成的“延迟链终止”。这种方法的基本原理是基于我们对锁定碳环核苷的发现（参见项目Z 01 BC 006174），其中我们表明，含有锁定在North构象中的假糖的核苷可以有效地阻断HIV-1 RT的DNA合成，并克服由于HIV-1 RT抗性变体中的切除而导致的耐药性。在该项目中，我们提出了用结构上更简单的带有4 ′-取代基的常规核苷是否可以实现相同目的的问题。为了研究4 '-烷基大小的重要性，合成了4'-甲基和4 '-乙基类似物。4 '-乙基类似物由于其大小而表现为严格的链终止剂，而4'-甲基类似物表现为延迟的链终止剂。胸腺嘧啶4 '-甲基类似物的研究正在进行中，以确定其在避免耐药HIV RT典型切除反应方面的功效。2)2 '，3'-双脱氧双环3.1.0己烯核苷。在确定构象锁定类似物North-MCD 4 T是非常有效的抗艾滋病毒药物后，正在研究South等效类似物。胸腺嘧啶和腺嘌呤类似物的合成已完成，鸟嘌呤和胞嘧啶类似物的合成正处于高级阶段。

The development of nucleoside analogues with novel mechanisms of action capable of overcoming HIV resistance is the main focus of this project. Current emphasis include two main classes of structures: 1) 4'-alkyl-2'-deoxynucleosides. These compounds were synthesized with the objective of achieving "delayed chain termination" of viral DNA synthesis catalyzed by HIV reverse transcriptase. The rationale for this approach was based on our findings with locked carbocyclic nucleosides (see project Z01 BC 006174) where we showed that a nucleoside containing a pseudosugar locked in the North conformation could efficiently block DNA synthesis by HIV-1 RT and overcome drug resistance due to excision in resistant variants of HIV-1 RT. In this project, we addressed the question of whether the same objective was achievable with structurally simpler conventional nucleosides bearing a 4'-substituent. In order to investigate the importance of the size of the 4'-alkyl group, the 4'-Methyl and 4'-Ethyl analogues were synthesized. The 4'-Ethyl analogue because of its size behaved as a strict chain terminator, whereas the 4'-Methyl analogue behaved as a delayed chain terminator. Studies with the 4'-Methyl analogue of thymine are in progress to determine its efficacy in avoiding the excision reaction typical of resistant HIV RTs. 2) 2',3'-Dideoxybicyclo3.1.0hexene nucleosides. Having identified the conformationally locked analogues North-MCD4T as a very effective anti-HIV agent, the South equivalent analogues are being pursued. Syntheses of the thymine and adenine analogues have been completed and the guanine and cytosine analogues are at an advanced stage.