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.
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: Donald Lavelle; Kestis Vaitkus; Yonghua Ling; Maria A Ruiz; Reda Mahfouz; Kwok Peng Ng; Soledad Negrotto; Nicola Smith; Pramod Terse; Kory J Engelke; Joseph Covey; Kenneth K Chan; Joseph Desimone; Yogen Saunthararajah Journal: Blood Date: 2011-12-07 Impact factor: 22.113
Authors: M A Vodicka; W C Goh; L I Wu; M E Rogel; S R Bartz; V L Schweickart; C J Raport; M Emerman Journal: Virology Date: 1997-06-23 Impact factor: 3.616
Authors: Stijn L W Koolen; Petronella O Witteveen; Robert S Jansen; Marlies H G Langenberg; Roelien H Kronemeijer; Annemarie Nol; Ignacio Garcia-Ribas; Sophie Callies; Karim A Benhadji; Christopher A Slapak; Jos H Beijnen; Emile E Voest; Jan H M Schellens Journal: Clin Cancer Res Date: 2011-07-13 Impact factor: 12.531
Authors: Oxana V Denisova; Laura Kakkola; Lin Feng; Jakob Stenman; Ashwini Nagaraj; Johanna Lampe; Bhagwan Yadav; Tero Aittokallio; Pasi Kaukinen; Tero Ahola; Suvi Kuivanen; Olli Vapalahti; Anu Kantele; Janne Tynell; Ilkka Julkunen; Hannimari Kallio-Kokko; Henrik Paavilainen; Veijo Hukkanen; Richard M Elliott; Jef K De Brabander; Xavier Saelens; Denis E Kainov Journal: J Biol Chem Date: 2012-08-21 Impact factor: 5.157
Authors: J L Abbruzzese; R Grunewald; E A Weeks; D Gravel; T Adams; B Nowak; S Mineishi; P Tarassoff; W Satterlee; M N Raber Journal: J Clin Oncol Date: 1991-03 Impact factor: 44.544
Authors: Christine L Clouser; Colleen M Holtz; Mary Mullett; Duane L Crankshaw; Jacquie E Briggs; Jay Chauhan; Ilze Matise VanHoutan; Steven E Patterson; Louis M Mansky Journal: PLoS One Date: 2011-01-14 Impact factor: 3.240
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