An investigation into the anti-HIV activity of 2′,3′-didehydro-2′,3′-dideoxyuridine (d4U) and 2′,3′-dideoxyuridine (ddU) phosphoramidate 'ProTide' derivatives
An investigation into the anti-HIV activity of 2′,3′-didehydro-2′,3′-dideoxyuridine (d4U) and 2′,3′-dideoxyuridine (ddU) phosphoramidate 'ProTide' derivatives
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DOI：
10.1039/b904276h
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发表时间：
2009-01-01
影响因子：
3.2
通讯作者：
McGuigan, Christopher
中科院分区：
文献类型：
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作者：
Mehellou, Youcef;Balzarini, Jan;McGuigan, Christopher
作为我们对2‘，3’-二氢-2‘，3’-二脱氧尿苷(D4U)，2‘，3’-二脱氧尿苷(DDU)及其‘ProTide’抗HIV活性研究的一部分，我们制备并评价了一系列d4U和dDu芳基三酯的抗HIV活性。除了阐明SAR特征外，我们还对d4U和ddu进行了分子模拟研究，以探索激活这两个核苷类似物所需的第一步磷酸化。总体而言，应用磷酰胺化方法将不活跃的ddu转变为中等活性的抗艾滋病毒药物，而d4u并非如此。对d4U磷酸盐代谢的酶分析表明，磷酰胺基序被有效地切割以释放d4U单磷酸盐。因此，糟糕的第二和/或第三步磷酸化可能是在这种情况下实际上缺乏抗HIV活性的最有可能的原因。
As part of our studies on the anti-HIV activities of 2',3'-didehydro-2',3'-dideoxyuridine (d4U), 2',3'-dideoxyuridine (ddU) and their 'ProTides', we have prepared and evaluated the anti-HIV activity of a range of d4U and ddU aryl triester phosphoramidates. Besides elucidating SAR characteristics, we performed molecular modelling studies on both d4U and ddU in order to probe the first phosphorylation step required for the activation of these two nucleoside analogues. Overall, the application of the phosphoramidate approach turned the inactive ddU to a moderately active anti-HIV agent, while this was not the case with d4U. Enzymatic assays investigating the metabolism of d4U phosphoramidates revealed an efficient cleavage of the phosphoramidate motif to release the d4U monophosphate. Thus, a poor second and/or third phosphorylation step may be the most likely reason for the virtual lack of anti-HIV activity in this case.