Synthesis and anti-hepatitis B virus activity of 9-(2-deoxy-2-fluoro-β-L-arabinofuranosyl)purine nucleosides

Since the discovery of 2‘-fluoro-5-methyl-β-l-arabinofuranosyluracil (l-FMAU) as a potent anti-HBV and anti-EBV agent, we have studied the structure−activity relationships of 2‘-deoxy-2‘-fluoro-β-l-arabinofuranosylpyrimidine nucleosides as anti-HBV agents. Therefore it is rational to extend this study to the purine nucleosides. Thus, 3,5-di-O-benzoyl-2-deoxy-2-fluoro-β-l-arabinofuranosyl bromide (1), which was prepared from l-xylose via a multistep procedure, was coupled with several purines by the sodium salt method. From this general synthesis, 10 purine nucleosides containing the 2-deoxy-2-fluoro-β-l-arabinofuranosyl moiety have been obtained. The anti-HBV activity and toxicity of the synthesized nucleosides were evaluated in HepG2 2.2.15 cells. Among them, the adenine (10) and hypoxanthine (15) derivatives exhibit good in vitro anti-HBV activity (EC50 = 1.5 and 8 μM, respectively) without significant toxicity up to 200 μM.