Design, Synthesis, and Antiviral Activity of 2‘-Deoxy-2‘-fluoro-2‘-C-methylcytidine, a Potent Inhibitor of Hepatitis C Virus Replication
- 26 July 2005
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 48 (17) , 5504-5508
- https://doi.org/10.1021/jm0502788
Abstract
The pyrimidine nucleoside beta-d-2‘-deoxy-2‘-fluoro-2‘-C-methylcytidine (1) was designed as a hepatitis C virus RNA-dependent RNA polymerase (HCV RdRp) inhibitor. The title compound was obtained by a DAST fluorination of N4-benzoyl-1-(2-methyl-3,5-di-O-benzoyl-β-d-arabinofuranosyl]cytosine (6) to provide N4-benzoyl-1-[2-fluoro-2-methyl-3,5-di-O-benzoyl-β-d-ribofuranosyl]cytosine (7a). The protected 2‘-C-methylcytidine (7c) was obtained as a byproduct from the DAST fluorination and allowed for the preparation of two biologically active compounds from a common precursor. Compound 1 and 2‘-C-methylcytidine were assayed in a subgenomic HCV replicon assay system and found to be potent and selective inhibitors of HCV replication. Compound 1 shows increased inhibitory activity in the HCV replicon assay compared to 2‘-C-methylcytidine and low cellular toxicity.Keywords
This publication has 9 references indexed in Scilit:
- Inhibition of the Subgenomic Hepatitis C Virus Replicon in Huh-7 Cells by 2′-Deoxy-2′-FluorocytidineAntimicrobial Agents and Chemotherapy, 2004
- Dynamics of Subgenomic Hepatitis C Virus Replicon RNA Levels in Huh-7 Cells after Exposure to Nucleoside AntimetabolitesJournal of Virology, 2003
- Ribonucleoside Analogue That Blocks Replication of Bovine Viral Diarrhea and Hepatitis C Viruses in CultureAntimicrobial Agents and Chemotherapy, 2003
- Polymerization of 2′-fluoro- and 2′-O-methyl-dNTPs by human DNA polymerase α, polymerase γ, and primaseBiochemical Pharmacology, 2000
- New Synthesis of a Protected Ketonucleoside by a Non-Cryogenic Oxidation with TFAA/DMSO1Organic Process Research & Development, 2000
- Synthesis of 4-substituted carbocyclic 2,3-dideoxy-3-C-hydroxymethyl nucleoside analogues as potential anti-viral agentsTetrahedron, 1999
- Structure-stability relationships of gadolinium(III) ion complexes for magnetic resonance imagingJournal of Medicinal Chemistry, 1991
- A Simple and Convenient Method for the Selective N-Acylations of Cytosine NucleosidesNucleosides, Nucleotides and Nucleic Acids, 1989
- New syntheses of 2′-C-methylnucleosides starting from d-glucose and d-riboseCarbohydrate Research, 1987