title: Characterization of permeability, stability and anti-HIV-1 activity of decitabine and gemcitabine divalerate prodrugs.
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.
authors.affiliation: Institute for Molecular Virology, University of Minnesota, Minneapolis, MN, USA. cclouser@umn.edu.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Clouser
authors.forename: Laurent
authors.initials: L
authors.lastname: Bonnac
authors.forename: Louis M
authors.initials: LM
authors.lastname: Mansky
authors.forename: Steven E
authors.initials: SE
authors.lastname: Patterson
mesh_terms: D019380:Anti-HIV Agents / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000187:drug effects; D000077209:Decitabine; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D004355:Drug Stability; D057809:HEK293 Cells; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006207:Half-Life; D006801:Humans; D006863:Hydrogen-Ion Concentration; D010539:Permeability; D011355:Prodrugs / Q000378:metabolism*; D000093542:Gemcitabine
chemical_list: D019380:Anti-HIV Agents; D011355:Prodrugs; D003841:Deoxycytidine; D000077209:Decitabine; D001374:Azacitidine; D000093542:Gemcitabine