Selective inhibition of Human Immunodeficiency Virus type 1 (HIV-1) by a novel family of tricyclic nucleosides

Nucleoside 1, with an unusual tricyclic carbohydrate moiety, specifically inhibits HIV-1 replication while being inactive against HIV-2 or other (retro) viruses. In an attempt to increase the inhibitory efficacy against HIV-1, and to further explore the structural features required for anti-HIV-1 activity, different types of modifications have been carried out on this prototype compound. These include substitution of the ethoxy group at the C-400 position by alkoxy groups of different length, branching, conformational freedom or functionalization. In addition, the 400-ethoxy group has been removed or substituted by other functional groups. The role of the tert-butyldimethylsilyl (TBDMS) group at the 20 position has also been studied by preparing the corresponding 20-deprotected derivative or by replacing it by other silyl (terthexyldimethylsilyl) or acyl (acetyl) moieties. Finally, the thymine of the prototype compound has been replaced by N-3-methylthymine, uracil or thiophenyl. Some of these compounds were endowed with a 6- to 7-fold higher selectivity than the prototype 1. The tricyclic nucleosides here described represent a novel type of selective anti HIV-1 inhibitors, targeted at the HIV-1-encoded reverse transcriptase.
We thank Susana Ruiz, Ann Absillis and Leen Ingels for excellent technical assistance. The Spanish MEC/MCINN (Project SAF 2009- 13914-C02-01), the Spanish CSIC (Project PIF 08-019-2) and the Concerted Research Actions of the K.U. Leuven (GOA 10/014) are also acknowledged for financial support. The Spanish CSIC (JAEDoc Program) and European Science Foundation (ESF) are also acknowledged for a JAE-Doc contract to M.-C. Bonache.