Synthesis, structure-activity relationships, and drug resistance of beta-d-3'-fluoro-2',3'-unsaturated nucleosides as anti-HIV Agents.
Synthesis, structure-activity relationships, and drug resistance of beta-d-3'-fluoro-2',3'-unsaturated nucleosides as anti-HIV Agents.
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DOI：
10.1021/jm040027j
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发表时间：
2004-05
影响因子：
7.3
通讯作者：
Wen Zhou;G. Gumina;Youhoon Chong;Jianing Wang;R. Schinazi;C. K. Chu
中科院分区：
文献类型：
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作者：
Wen Zhou;G. Gumina;Youhoon Chong;Jianing Wang;R. Schinazi;C. K. Chu
我们最近的研究表明，d-和L-2‘-氟-2’，3‘-不饱和核苷(d-和L-2’-F-d4ns)对HIV-1和HBV有中等到强烈的抗病毒活性。作为这些发现的延伸，合成了β-d-3‘-氟-2’，3‘-不饱和核苷作为潜在的抗病毒药物。以2，3-O-异亚丙基-d-甘油醛1为原料，在酸性条件下经开环反应制得关键中间体(2S)-5-(1，3-dioxolan)-1-benzoyloxy-3，3-difluoropentan-2-ol 6。醋酸酯7与硅烷化的嘌呤和嘧啶碱缩合，产生α和β异构体。然后用t-BuOK处理3‘，3’-二氟核苷，得到所需的3‘-氟不饱和核苷。我们研究了d-3‘-氟-2’，3‘-不饱和核苷在人外周血单核细胞中抗HIV-1的构效关系，从中发现胞嘧啶衍生物26是合成的化合物中最有效的。为了了解作用模式和耐药性，特别是氟的作用，我们对胞苷类似物d-3‘F-D4C进行了分子模拟研究，发现计算的相对结合能与活性/耐药性数据之间有很好的相关性。我们的模型还显示了3‘-氟和2’，3‘双键的相互作用，这可以与观察到的生物数据相关联。在3‘和2’位的氟取代差异可能解释了在2‘-氟化系列中观察到的与拉米夫定较高的交叉耐药性。
Our recent studies demonstrated that d- and l-2'-fluoro-2',3'-unsaturated nucleosides (d- and l-2'-F-d4Ns) display moderate to potent antiviral activities against HIV-1 and HBV. As an extension of these findings, beta-d-3'-fluoro-2',3'-unsaturated nucleosides were synthesized as potential antiviral agents. The key intermediate (2S)-5-(1,3-dioxolan)-1-benzoyloxy-3,3-difluoropentan-2-ol 6 was prepared from 2,3-O-isopropylidene-d-glyceraldehyde 1, which was converted to 5-O-benzoxy-d-2-deoxy-3,3-difluoropentofuranosyl acetate 7 by the ring-closure reaction under acidic conditions. The acetate 7 was condensed with silylated purine and pyrimidine bases, which produced the alpha and beta isomers. The 3',3'-difluoro nucleosides were then treated with t-BuOK to give the desired 3'-fluoro-unsaturated nucleosides. We studied the structure-activity relationships of d-3'-fluoro-2',3'-unsaturated nucleosides against HIV-1 in human peripheral blood mononuclear cells, from which we found that the cytosine derivative 26 was the most potent among the synthesized compounds. To understand the mode of action and drug resistance profile, with particular regard to the role of fluorine, we performed the molecular modeling studies of the cytidine analogue d-3'F-d4C and found a good correlation between calculated relative binding energies and activity/resistance data. Our model also shows interactions of the 3'-fluorine and the 2',3' double bond, which can be correlated to the observed biological data. Differences between fluorine substitution at the 3' and 2' positions may account for the higher cross-resistance with lamivudine observed in the 2'-fluorinated series.