Characterization of Permeability, Stability and Anti-HIV-1 Activity of Decitabine and Gemcitabine Divalerate Prodrugs. Issue 6 (December 2014)

• Record Type: Journal Article
• Authors: Clouser, Christine L; Bonnac, Laurent; Mansky, Louis M; Patterson, Steven E
• Is Part Of: Antiviral chemistry & chemotherapy. Volume 23:Issue 6(2014)
• Page Start: 223
• Page End: 230
• Publication Date: 2014-12
• Subjects: Antiviral agents -- Periodicals; Chemotherapy -- Periodicals; 615.7924
• DOI: 10.3851/IMP2682
• Languages: English
• ISSNs: 0956-3202

Abstract

Background: Over 25 drugs have been approved for the treatment of HIV-1 replication. All but one of these drugs is delivered as an oral medication. Previous studies have demonstrated that two drugs, decitabine and gemcitabine, have potent anti-HIV-1 activities and can work together in synergy to reduce HIV-1 infectivity via lethal mutagenesis. For their current indications, decitabine and gemcitabine are delivered intravenously. Methods: As an initial step towards the clinical translation of these drugs for the treatment of HIV-1 infection, we synthesized decitabine and gemcitabine prodrugs in order to increase drug permeability, which has generally been shown to correlate with increased bioavailability in vivo . In the present study we investigated the permeability, stability and anti-HIV-1 activity of decitabine and gemcitabine prodrugs and selected the divalerate esters of each as candidates for further investigation. Results: Our results provide the first demonstration of divalerate prodrugs of decitabine and gemcitabine that are readily permeable, stable and possess anti-HIV-1 activity. Conclusions: These observations predict improved oral availability of decitabine and gemcitabine, and warrant further study of their ability to reduce HIV-1 infectivity in vivo .