title: Synthesis, antiviral activity, cytotoxicity and cellular pharmacology of l-3'-azido-2',3'-dideoxypurine nucleosides.
abstract: Microwave-assisted optimized transglycosylation reactions were used to prepare eleven modified l-3'-azido-2',3'-dideoxypurine nucleosides. These l-nucleoside analogs were evaluated against HIV and hepatitis B virus. The l-3'-azido-2',3'-dideoxypurines nucleosides were metabolized to nucleoside 5'-triphosphates in primary human lymphocytes, but exhibited weak or no antiviral activity against HIV-1. The nucleosides were also inactive against HBV in HepG2 cells. Pre-steady state kinetic experiments demonstrated that the l-3'-azido-2',3'-dideoxypurine triphosphates could be incorporated by purified HIV-1 reverse transcriptase, although their catalytic efficiency (k(pol)/K(d)) of incorporation was low. Interestingly, a phosphoramidate prodrug of l-3'-azido-2',3'-dideoxyadenosine exhibited anti-HIV-1 activity without significant toxicity.
authors.affiliation: Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, and the Veterans Affairs Medical Center, Decatur, GA 30033, USA.
authors.forename: Hong-Wang
authors.initials: HW
authors.lastname: Zhang
authors.forename: Mervi
authors.initials: M
authors.lastname: Detorio
authors.forename: Brian D
authors.initials: BD
authors.lastname: Herman
authors.forename: Sarah
authors.initials: S
authors.lastname: Solomon
authors.forename: Leda
authors.initials: L
authors.lastname: Bassit
authors.forename: James H
authors.initials: JH
authors.lastname: Nettles
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Obikhod
authors.forename: Si-Jia
authors.initials: SJ
authors.lastname: Tao
authors.forename: John W
authors.initials: JW
authors.lastname: Mellors
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sluis-Cremer
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Coats
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Schinazi
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002460:Cell Line; D006031:Glycosylation; D015497:HIV-1 / Q000187:drug effects; D006515:Hepatitis B virus / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D008872:Microwaves; D008958:Models, Molecular; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000998:Antiviral Agents; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors