Synthesis and Antiviral Activity of Purine 2′,3′-Dideoxy-2′,3′-Difluoro-D-Arabinofuranosyl Nucleosides

Abstract

9-(2′,3′-Dideoxy-2′,3′-difluoro-β-D-arabinofuranosyl)adenine (20), 2-chloro-9-(2′,3′-dideoxy-2,3-difluoro-β-D-arabinofuranosyl)adenine (22), as well as their respective α-anomers 21 and 23, were synthesized by the nucleobase anion glycosylation of intermediate 5-O-benzoyl-2,3-dideoxy-2,3-difluoro-α-D-arabinofuranosyl bromide (13) starting from methyl 5-O-benzyl-3-deoxy-3-fluoro-α-D-ribofuranoside (3) and methyl 5-O-benzoyl-α-D-xylofuranoside (10). These compounds were evaluated as potential inhibitors of HIV-1 and hepatitis C virus in human PBM and Huh-7 Replicon cells, respectively. The adenosine analog 20 demonstrated potent activity against HIV-1 in primary human lymphocytes with no apparent cytotoxicity. Conformation of pentofuranose ring of nucleoside 20 in solution was studied by PSEUROT calculations.