Synthesis and Anti-HIV and Anti-HBV Activities of 2‘-Fluoro-2‘,3‘-unsaturated l-Nucleosides

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Abstract
The synthesis of l-nucleoside analogues containing 2‘-vinylic fluoride was accomplished by direct condensation method, and their anti-HIV and anti-HBV activities were evaluated in vitro. The key intermediate 8, the sugar moiety of our target compounds, was prepared from 1,2-O-isopropylidene-l-glyceraldehyde via (R)-2-fluorobutenolide intermediate 5 in five steps. Coupling of the acetate 8 with the appropriate heterocycles (silylated uracil, thymine, N4-benzoylcytosine, N4-benzoyl-5-fluorocytosine, 6-chloropurine, and 6-chloro-2-fluoropurine) in the presence of Lewis acid afforded a series of 2‘-fluorinated l-nucleoside analogues (15−18, 23−26, 36−45). The newly synthesized compounds were evaluated for their antiviral activities against HIV-1 in human peripheral blood mononuclear (PBM) cells and HBV in 2.2.15 cells. Cytosine 23, 5-fluorocytosine 25, and adenine 36 derivatives exhibited moderate to potent anti-HIV (EC50 0.51, 0.17, and 1.5 μM, respectively) and anti-HBV (EC50 0.18, 0.225, and 1.7 μM, respectively) activities without significant cytotoxicity up to 100 μM in human PBM, Vero, CEM, and HepG2 cells.