Synthesis and anti-HIV and anti-HBV activities of 2 '-fluoro-2 ',3 '-unsaturated L-nucleosides

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 moie ty of our target compounds, was prepared from 1,2-O-isopropylidene-L-glycer aldehyde via (R)-2-fluorobutenolide intermediate 5 in five steps. Coupling of the acetate 8 with the appropriate heterocycles (silylated uracil, thymi ne, N-4-benzoylcytosine, N-4-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 (1.5-18, 23-26, 36-45). The newly sy nthesized compounds were evaluated for their antiviral activities against H TV-1 in human peripheral blood mononuclear (PBM) cells and HBV in 2.2.15 ce lls. Cytosine 23, 5-fluorocytosine 25, and adenine 36 derivatives exhibited moderate to potent anti-HIV (EC50 0.51, 0.17, and 1.5 mu M, respectively) and anti-HBV (EC50 0.18, 0.225, and 1.7 mu M, respectively) activities with out significant cytotoxicity up to 100 mu M in human PBM, Vero, GEM, and He pG2 cells.