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New 3'-azido-3'-deoxythymidin-5'-yl O-(4-hydroxyalkyl or -alkenyl or -alkylepoxide) carbonate prodrugs: synthesis and anti-HIV evaluation.

Abstract：

:New 5'-O-carbonate prodrugs of zidovudine (AZT) have been synthesized in order to enhance its uptake by HIV-1 infected cells, to improve its anti-HIV potency, and to optimize the intramolecular cyclic rearrangement process related to the 5'-O-(4-hydroxybutyl) carbonate moiety. Evidence of this prodrug rearrangement was confirmed by comparison of the serum half-lives of the 3'-azido-3'-deoxythymidin-5'-yl O-(4-hydroxyalkyl or -alkenyl or -alkylepoxide) carbonate prodrugs with our thermodynamic predictions. Interestingly, these 5'-O-carbonate prodrug series show increased anti-HIV potencies in conjunction with, or without, reduced cytotoxicity as compared to AZT that lead to a gain in selectivity indexes. The cytotoxicity of AZT could be reduced with these 5'-O-carbonate prodrug series by delaying the 5'-O-glucuronidation of AZT, which is one of the major limitations of AZT.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Vlieghe P,Clerc T,Pannecouque C,Witvrouw M,De Clercq E,Salles JP,Kraus JL

doi

10.1021/jm010863i

keywords:

subject

Has Abstract

pub_date

2001-08-30 00:00:00

pages

3014-21

issue

18

eissn

0022-2623

issn

1520-4804

pii

jm010863i

journal_volume

44

pub_type

杂志文章

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