Synthesis, antiviral activity, cytotoxicity and cellular pharmacology of l-3'-azido-2',3'-dideoxypurine nucleosides

  • Eur J Med Chem. 2011 Sep;46(9):3832-44. doi: 10.1016/j.ejmech.2011.05.051.
Hong-Wang Zhang  1 ,  Mervi Detorio ,  Brian D Herman ,  Sarah Solomon ,  Leda Bassit ,  James H Nettles ,  Aleksandr Obikhod ,  Si-Jia Tao ,  John W Mellors ,  Nicolas Sluis-Cremer ,  Steven J Coats ,  Raymond F Schinazi
Affiliations
  • 1. Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, and the Veterans Affairs Medical Center, Decatur, GA 30033, USA.
PMID: 21700368 DOI: 10.1016/j.ejmech.2011.05.051
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.