Aryl phosphoramidate derivatives of d4T have improved anti-HIV efficacy in tissue culture and may act by the generation of a novel intracellular metabolite

被引:220
作者
McGuigan, C
Cahard, D
Sheeka, HM
DeClercq, E
Balzarini, J
机构
[1] Welsh School of Pharmacy, University of Wales Cardiff, Cardiff, CFI 3XF, King Edward VII Avenue
[2] Department of Chemistry, University of Southampton, Southampton
[3] Rega Institute for Medical Research, Katholieke Universiteit of Leuven, B-3000, Leuven
关键词
D O I
10.1021/jm950605j
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
New phosphate derivatives of the anti-HIV nucleoside analogue d4T were prepared as potential membrane-soluble prodrugs of the bioactive free nucleotide. The enhanced antiviral potency and/or reduced cytotoxicity of the derivatives leads to an increase in selectivity relative to the parent nucleoside analogue. Moreover, the derivatives appear to bypass the dependence of the nucleoside on thymidine kinase-mediated activation, retaining full activity in thymidine kinase-deficient cells. This strongly suggests the successful intracellular delivery of free nucleotides by the masked phosphate triester prodrugs. This is further confirmed by studies using radiolabeled compound which clearly demonstrate the generation of d4T mono-, di- and triphosphates from the prodrug, even in thymidine kinase-deficient cells. Moreover, we herein report the generation of a new metabolite, a partially hydrolyzed phosphate diester, alaninyl d4T monophosphate. We suggest that at least part of the antiviral action of the prodrugs derives from the intracellular generation of such novel diesters which may add considerable weight to the suggested further preclinical development of the phosphate prodrugs.
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页码:1748 / 1753
页数:6
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