New 3‘-Azido-3‘-deoxythymidin-5‘-yl O-(4-Hydroxyalkyl or -Alkenyl or -Alkylepoxide) Carbonate Prodrugs: Synthesis and Anti-HIV Evaluation
| Autor: | Myriam Witvrouw, Jean-Louis Kraus, Patrick Vlieghe, Jean-Pierre Salles, Erik De Clercq, Thierry Clerc, Christophe Pannecouque |
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| Rok vydání: | 2001 |
| Předmět: |
Anti-HIV Agents
Stereochemistry viruses Epoxide Chemical synthesis Structure-Activity Relationship chemistry.chemical_compound Zidovudine Drug Stability Drug Discovery medicine Humans Structure–activity relationship Moiety Prodrugs heterocyclic compounds Cytotoxicity Cells Cultured Chemistry virus diseases biochemical phenomena metabolism and nutrition Prodrug Molecular Medicine Selectivity medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 44:3014-3021 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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