Phosphoramidate prodrugs of (-)-β-D-(2R,4R)-dioxolane-thymine (DOT) as potent anti-HIV agents

Antiviral Chemistry & Chemotherapy
Peiyuan WangMichael J Sofia

Abstract

Nucleoside reverse transcriptase inhibitors (NRTIs) are an effective class of agents that has played a vital role in the treatment of HIV infections. (-)-β-D-(2R,4R)-dioxolane-thymine (DOT) is a thymidine analogue that is active against wild-type and NRTI-resistant HIV-1 mutants. It has been shown that the anti-HIV activity of DOT is limited due to poor monophosphorylation. To further enhance the anti-HIV activity of DOT, an extensive structure-activity relationship analysis of phosphoramidate prodrugs of DOT monophosphate was undertaken. These prodrugs were evaluated for anti-HIV activity using Hela CD4 β-gal reporter cells (P4-CCR5 luc cells). Among the synthesized prodrugs, the 4-bromophenyl benzyloxy l-alanyl phosphate derivative of DOT was the most potent, with a 50% effective concentration of 0.089 μM corresponding to a 75-fold increase in activity relative to the parent nucleoside DOT with no increased cytotoxicity. The metabolic stability of a selected number of potent DOT phosphoramidates was also evaluated in simulated gastric fluid, simulated intestinal fluid, human plasma and liver S9 fractions. A series of new phosphoramidate prodrugs of DOT were prepared and evaluated as inhibitors of HIV replication in vitro. Met...Continue Reading

References

Mar 1, 1995·The Journal of Infectious Diseases·E A PetersenL M Dunkle
Mar 4, 2005·Journal of Medicinal Chemistry·Erik De Clercq
Apr 6, 2005·Bioorganic & Medicinal Chemistry·Christopher McGuiganMalcolm Mason
Sep 30, 2009·Journal of Medicinal Chemistry·Youcef Mehellou, Erik De Clercq
Aug 23, 2011·Bioorganic & Medicinal Chemistry Letters·Christopher McGuiganStanley Chamberlain

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Citations

Apr 2, 2014·European Journal of Medicinal Chemistry·Fabrizio PertusatiChristopher McGuigan
Aug 22, 2014·Chemical Reviews·Ugo PradereRaymond F Schinazi
Sep 10, 2013·ACS Medicinal Chemistry Letters·Lavanya BondadaRaymond F Schinazi

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