Synthesis of potential anti-HIV agents and prodrugs: Part I synthesis of L-3'-hydroxymethylnucleosides. Part II synthesis and pharmacokinetics of 3'-azido-2',3'-dideoxyuridine (AZDU) as prodrugs

Part I. The L-3′-hydroxymethylnucleosides were synthesized via the key intermediate carbohydrate, which was synthesized by first selectively protecting the 1′- and 2′-hydroxyl groups followed by selective tosylation of the 5′-hydroxyl. The tosyl moiety was then replaced by a benzyl ether. The benzyl ether underwent Dess-Martin oxidation to afford the ketone. The ketone was subjected to Wittig oleofination to afford the alkene followed by regioselective hydroboration. The alcohol was fully acetylated using acetic acid, acetic anhydride and sulfuric acid to obtain the key intermediate. The key intermediate was condensed with silylated base using Vorbrüggen's methodology. The synthesized compounds were found to lack anti-HIV-1 and anti-HBV activities.; Part II. Various 5′- O- and N3-derivatives of 3 ′-azido-2′,3′-dideoxyuridine (AZDU) were synthesized as prodrugs. Among the compounds synthesized, valinyl ester AZDU (Val-AZDU) significantly increase the half-life of parent compound in rats. Val-AZDU was found to have anti-HIV activity comparable to that of AZDU in PBM cells.