Synthesis and anti-hepatitis B virus activity of 9-(2-deoxy-2-fluoro-beta-L-arabinofuranosyl) purine nucleosides.
Since the discovery of 2'-fluoro-5-methyl-beta-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-beta-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-beta-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-beta-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 microM, respectively) without significant toxicity up to 200 microM.
Ma
T
T
Department of Medicinal Chemistry, College of Pharmacy, University of Georgia, Athens 30602, USA.
Lin
J S
JS
Newton
M G
MG
Cheng
Y C
YC
Chu
C K
CK
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006515:Hepatitis B virus / Q000187:drug effects*; D008956:Models, Chemical; D008958:Models, Molecular; D012984:Software; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D001086:Arabinofuranosyluracil; C034935:clevudine