Dideoxynucleosides as Potential Anti-AIDS Drugs

含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传统脱氧核苷底物中存在的关键3-OH基团(链延伸所需)，但添加4-烷基(甲基和乙基)以干扰链延伸步骤。含有4-甲基和4-乙基的胸腺嘧啶核苷系列的合成已经成功完成，并且最近发表了结果(J.Mol。比奥尔。2007,371,873-882)。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。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地磷酸化，又能在感染细胞中对HIV具有极强的抗药性。这代表了这类化合物的第一次成功设计，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)链终止子，完成了以胸腺嘧啶、胞嘧啶、鸟嘌呤和腺嘌呤为核苷酸碱基的构象锁定和平坦的双环[3.1.0]六-3-烯核苷的合成。在细胞培养中，这些化合物都没有抗HIV的活性。今年，我们还完成了腺嘌呤双环[3.1.0]己烷核苷的合成，该核苷含有一个膦亚甲基，从而绕过了细胞激酶的磷酸化需要。该模板模仿三糖的主干。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.