Dideoxynucleosides as Potential Anti-AIDS Drugs

对带有常规脱氧核糖骨架的抗HIV核苷的研究仍在继续。所用的基本原理包括保持常规脱氧核苷底物中存在的关键3-OH基团（扩链所需），但添加4-烷基（甲基和乙基）以干扰扩链步骤。成功地完成了带有4-甲基和4-乙基的胸苷系列的合成，并且最近发表了结果（J. Mol. Biol. 2007，371，873-882）。4-甲基类似物表现出优良的性能作为延迟链终止剂时，在体外用于抗HIV-RT作为5-三磷酸，但未能被细胞激酶识别。另一方面，最近合成的相应的4-甲基脱氧腺苷系列提供了一种化合物，它既能被细胞激酶成功磷酸化，又能在感染细胞中对HIV极其有效。这代表了该类化合物的首次成功设计，该化合物能够被细胞激酶激活并能够作为病毒DNA合成的有效延迟（动力学延迟）链终止剂。完成了在含有胸腺嘧啶、胞嘧啶、鸟嘌呤和腺嘌呤作为核碱基的假旋转循环的南半球中构象锁定和平坦的双环[3.1.0]己-3-烯核苷的合成。这些化合物在细胞培养物中均无抗HIV活性。今年，我们还完成了带有膦酰基甲基的腺嘌呤双环[3.1.0]己烷核苷的合成，以绕过细胞激酶磷酸化的需要。模板模拟苏糖骨架。将进行生物学研究。

The study of anti-HIV nucleosides bearing a conventional deoxyribose backbone continues. The rationale used involves maintaining the critical 3-OH group present in conventional deoxynucleoside substrates (required for chain extension), but adding a 4-alkyl group (methyl and ethyl) to interfere with the chain elongation step. Synthesis of the thymidine series bearing 4-methyl and 4-ethyl groups was successfully completed and the results recently published (J. Mol. Biol. 2007, 371, 873-882). 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 recent synthesis of the corresponding 4-methyl deoxyadenosine series, on the other hand, provided a compound that is both successfully phosphorylated by cellular kinases and extremely potent against HIV in infected cells. This represents the first successful design of a compound in this class capable of being activated by cellular kinases and able to function as an effective delay (kinetic delay) chain terminator of viral DNA synthesis, The synthesis of conformationally locked and flat bicyclo[3.1.0]hex-3-ene nucleosides in the south hemisphere of the pseudorotational cycle containing thymine, cytosine, guanine, and adenine as nucleobases was completed. None of the compounds were active against HIV in cell culture. This year we also completed the synthesis of an adenine bicyclo[3.1.0]hexane nucleoside bearing a phosphonomethyl group to bypass the need of phosphorylation by cellular kinases. The template mimics a threose backbone. Biological studies will be performed.