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

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 (kpol/Kd) of incorporation was low. Interestingly, a phosphoramidate prodrug of l-3′-azido-2′,3′-dideoxyadenosine exhibited anti-HIV-1 activity without significant toxicity.

A series of l-3′-azido-2′,3′-dideoxypurine nucleosides were prepared via microwave-assisted transglycosylation and evaluated against HIV and hepatitis B virus. Interestingly, a phosphoramidate prodrug of l-3′-azido-2′,3′-dideoxyadenosine exhibited anti-HIV-1 activity without significant toxicity.Figure optionsDownload as PowerPoint slideHighlights
► Microwave transglycosylation prepared l-3′-azido-2′,3′-dideoxypurine nucleosides.
► The L-nucleosides had weak or no antiviral activity against HIV-1 and HBV.
► Pre-steady-state kinetics and cellular pharmacology clarified the results.
► An l-nucleoside phosphoramidate had anti-HIV-1 activity without significant toxicity.