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

McGuigan, Christopher, Cahard, Dominique, Sheeka, Hendrika M., De Clercq, Erik and Balzarini, Jan 1996. Aryl phosphoramidate derivatives of d4T have improved anti-HIV efficacy in tissue culture and may act by the generation of a novel intracellular metabolite. Journal of Medicinal Chemistry 39 (8) , pp. 1748-1753. 10.1021/jm950605j

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Abstract

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > RM Therapeutics. Pharmacology
Publisher: ACS Publications
ISSN: 0022-2623
Last Modified: 14 Oct 2017 20:54
URI: http://orca.cf.ac.uk/id/eprint/46446

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