Characterization of Hepatitis B Virus Inhibition by Novel 2′-Fluoro-2′,3′-Unsaturated Beta-D- and l-nucleosides

The clinical emergence of lamivudine and adefovir resistance mutations on prolonged therapy further necessitates the development of additional drugs for the treatment of hepatitis B virus (HBV) infections. We have evaluated a number of novel 2′-fluoro-2′,3′-unsaturated d- and l-nucleosides for their anti-HBV activity in the HepG2–2.2.15 cell system. The most potent nucleosides were β-l-2′-fluoro-2′,3′-dideoxy-2′,3′-didehydrocytidine (l-2′-Fd4C) and β-l-2′-fluoro-2′,3′-dideoxy-2′,3′-didehydro-5-fluorocytidine (l-2′-Fd4FC) with median effective concentrations (EC50) of 0.002 μM and 0.004 μM, respectively. The d-enantiomers of the 2′-fluoro-substituted cytidine analogues in this series showed activity, with the 5-fluorocytidine (d-2′-Fd4FC) being the most potent (EC50=0.05 μM). The active compounds were not cytotoxic to a number of cell lines or to bone marrow progenitor cells. Furthermore, mitochondrial DNA synthesis and function were not affected by these nucleosides. l-2′-Fd4C did not affect viral transcr...