Structure-activity relationships of 1-(2-deoxy-2-fluoro-beta-L-arabinofuranosyl)pyrimidine nucleosides as anti-hepatitis B virus agents

Since 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil (L-FMAU) has been shown to be a potent anti-HBV agent in vitro, it was of interest to study the structure-activity relationships of related nucleosides. Thus, a series of 1-(2-deoxy-2-fluoro-beta-L-arabinofuranosyl)pyrimidine nucleosides have been synthesized and evaluated for antiviral activity against HBV in 2.2.15 cells. For this study, L-ribose was initially used as the starting material. Due to the commercial cost of L-ribose, we have developed an efficient procedure for the preparation of L-ribose derivative 6. Starting from L-xylose, 6 was obtained in an excellent total yield (70%) through the pyridinium dichromate oxidation of the 3-OH group followed by stereoselective reduction with NaBH4. It was further converted to the 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-alpha-L-arabinofuranose (10), which was then condensed with various 5-substituted pyrimidine bases to give the nucleosides. Among the compounds synthesized, the lead compound, L-FMAU (13), exhibited the most potent anti-HBV activity (EC(50) 0.1 mu M). None of the other uracil derivatives showed significant anti-HBV activity up to 10 mu M. Among the cytosine analogues, the cytosine (27) and 5-iodocytosine (35) derivatives showed moderately potent anti-HBV activity (EC(50) 1.4 and 5 mu M, respectively). The cytotoxicity of these nucleoside analogues has also been assessed in 2.2.15 cells as well as CEM cells. None of these compounds displayed any toxicity up to 200 mu M in 2.2.15 cells. Thus,compound 13 (L-FMAU), 27, and 35 showed a selectivity of over 2000, 140, and 40, respectively.