STRUCTURE-ACTIVITY-RELATIONSHIPS OF -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 be en shown to be a potent anti-HBV agent in vitro, it was of interest to study the structure-activity relationships of related nucleosides. Th us, a series of -deoxy-2-fluoro-beta-L-arabinofuranosyl)pyrimidine nuc leosides have been synthesized and evaluated for antiviral activity ag ainst 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 t otal yield (70%) through the pyridinium dichromate oxidation of the 3- OH group followed by stereoselective reduction with NaBH4. It was furt her converted to the O-benzoyl-2-deoxy-2-fluoro-alpha-L-arabinofuranos e (10), which was then condensed with various 5-substituted pyrimidine bases to give the nucleosides. Among the compounds synthesized, the l ead compound, L-FMAU (13), exhibited the most potent anti-HBV activity (EC(50) 0.1 mu M). None of the other uracil derivatives showed signif icant anti-HBV activity up to 10 mu M. Among the cytosine analogues, t he cytosine (27) and 5-iodocytosine (35) derivatives showed moderately potent anti-HBV activity (EC(50) 1.4 and 5 mu M, respectively). The c ytotoxicity 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), 2 7, and 35 showed a selectivity of over 2000, 140, and 40, respectively .