Research on L-Nucleosides. Synthesis and Biological Evaluation of a Series of L- and D-2’,3’-Dideoxy-3’-[Tris(methylthio)methyl]-β-Pentofuranosyl Nucleosides

Novel nucleoside analogues of both D and L enantiomeric series were prepared by coupling reaction between a 2′,3′-dideoxy-3′-modified furanose moiety and four different nucleobases. Though in all cases anomeric mixtures of nucleosides were obtained, the presence of the sterically bulky 3′-tris(methylthio)methyl group allowed a good stereoselectivity level. All the compounds of both enantiomeric series showed high IC50 values as HSV-1 TK inhibitors and scarce ability to be phosphorylated by HSV-1 TK. In order to overcome possible problems related to the first phosphorylation step and to facilitate the penetration of the molecule through the cellular membrane, a monophosphate prodrug containing a long lipophilic chain was synthesized. No appreciable antiviral activity was exhibited by this molecule. © 2002 Elsevier Science Ltd. All rights reserved.