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J Med Chem. 2001 Aug 30;44(18):3014-21.

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

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  • 1Laboratoire de Chimie Biomol√©culaire, Facult√© des Sciences de Luminy, 163 avenue de Luminy, case 901, 13288 Marseille Cedex 9, France.


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.

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