Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019163 (hepatitis B)
 38,309 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To begin an exploration of the structural parameters responsible for the activity of (+)-5'-noraristeromycin toward hepatitis B virus (HBV), three derivatives varied at the C-4' position have been prepared and evaluated. The syntheses began with a Mitsunobu coupling reaction of an appropriate cyclopentanol with 6-chloropurine. The products of these reactions were synthetically altered by standard ammonolysis and deprotection procedures to give the desired products. Evaluation of the new derivatives indicated that removal of the C-4' hydroxyl of (+)-5'-noraristeromycin increased its potency toward HBV by approximately 10-fold.
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PMID:Does the anti-hepatitis B virus activity of (+)-5'-noraristeromycin exist in its 4'-epimer and 4'-deoxygenated derivatives? 962 58

2'-Fluoro-6'-methylene carbocyclic adenosine (FMCA) is a potent and selective inhibitor of wild type as well as drug-resistant hepatitis B virus (HBV) mutants. FMCA demonstrated excellent anti-HBV activity against both adefovir-resistant and lamivudine-resistant double (rtL180M/rtM204V) mutants as well as in lamivudine/entecavir triple mutants (L180M+S202G+M204V) in vitro. Its monophosphate prodrug (FMCAP) demonstrated a greater than 12-fold increase of anti-HBV activity in comparison to that of the nucleoside without elevation of cellular toxicity. In the preliminary in vivo study in chimeric mice harboring the lamivudine/entecavir triple mutant, FMCAP effectively reduced HBV viral load, while entecavir was not effective. Therefore, it was of great interest to develop an efficient synthetic procedure to support the preclinical investigation. In this article, a new approach for the synthesis of FMCA from a readily available starting material (Vince lactam) in 16 steps is described. An efficient and practical methodology for stereospecific preparation of a versatile carbocyclic key intermediate, D-2'-fluoro-6'-methylene cyclopentanol 14, has been developed from diazotization, elimination, stereoselective epoxidation, fluorination, and oxidation-reduction sequence of the Vince lactam in 14 steps. The utility of D-2'-fluoro-6'-methylene cyclopentanol 14 is demonstrated in the preparation of FMCA using the Mitsunobu coupling to introduce the adenine base to synthesize the final nucleoside.
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PMID:Stereoselective synthesis of 2'-fluoro-6'-methylene carbocyclic adenosine via Vince lactam. 2469 70