Dideoxynucleosides as Potential Anti-AIDS Drugs

4'-乙基-2'-脱氧核苷（4'-EdN）是一类新的核苷类似物，具有抗多种HIV病毒（包括多种耐药克隆）的有效活性（Kodama等）。Antimicrob。药物化学，2001,45,1539)。虽然对一组选定的类似物报道了良好的选择性指数（约400-2600），但关于3'-OH基团及其在细胞毒性中的作用仍然存在一些担忧。为了研究这个问题，我们选择修改4'-乙基-2'-脱氧胞苷（4'-EdCyt）的结构，该化合物在光谱的最低范围内具有选择性指数，是最有效的化合物之一。去除3'-OH基团并不是一项微不足道的任务，它需要一种与4'-EdN系列完全不同的合成方法。从缩水甘油酯4-甲氧基苯基醚开始，13步后目标胞苷类似物[?]-4′-EddCyt)。该化合物的结构通过高分辨率核磁共振波谱和x射线晶体学得到了证实。该化合物在体外完全无活性(0.001 ？M -10 ？M)对抗HIV-1-LAI，这证明了3'-OH基团对抗病毒活性的至关重要。为了确定3'-OH的关键作用是否对激酶激活步骤或对DNA聚合的抑制至关重要，5'-三磷酸（?）合成-4′-EddCyt并在体外测试其对逆转录酶（RT）的抑制作用。5'-三磷酸被证明是非常有效的，这表明3'-OH的作用仅在细胞激酶激活时起关键作用。目前，我们正致力于D-和l -对映体的分离，以选择一种可绕过激酶激活步骤的前药物方法。对一系列新的构象受限的2'-脱氧和二脱氧双环[3.1.0]己烷类似物的进一步研究继续确定糖构象在DNA掺入后的RT抑制和链延伸中的作用。

4 '-Ethynyl-2'-deoxynucleosides (4'-EdN) represent a new class of nucleoside analogues endowed with potent activity against a wide spectrum of HIV viruses, including a variety of resistant clones (Kodama et al. Antimicrob. Agents Chemother. 2001, 45, 1539). Although favorable selectivity indices (ca. 400-2600) were reported for a select group of analogues, some concern still exists regarding the 3'-OH group and its role in cellular toxicity. To study this problem, we elected to modify the structure of 4'-ethynyl-2'-deoxycytidine (4'-EdCyt), a compound that was identified amongst the most potent ones having a selectivity index in the lowest range of the spectrum. The removal of the 3'-OH group was not a trivial task and required a totally different synthetic approach to the one used for the 4'-EdN series. Starting with glycidyl 4-methoxyphenyl ether, 13 steps later the target cytidine analogue [(?)-4'-EddCyt) was obtained. The structure of the compound was confirmed by high resolution NMR spectroscopy and X-ray crystallography. The compound was completely inactive in vitro (0.001 ?M -10 ?M) against HIV-1-LAI, which demonstrated the critical importance of the 3'-OH group for antiviral activity. In order to determine whether the critical role of the 3'-OH is essential for the kinase(s) activation step(s) or for the inhibition of DNA polymerization, the 5'-triphoshate of (?)-4'-EddCyt was synthesized and tested for inhibition of reverse transcriptase (RT) in vitro. The 5'-triphosphate proved to be quite potent indeed suggesting that the role of the 3'-OH is only critical during activation by cellular kinases. Currently, our efforts are being directed to the resolution of both D- and L-enantiomers in order to select a candidate for a pro-drug approach that would by-pass the kinase activation step. Additional studies on a novel series of conformationally constrained, 2'-deoxy and dideoxy bicyclo[3.1.0]hexane analogues continues to determine the role of sugar conformation in RT inhibition and chain elongation after DNA incorporation.