Abstract
Bicyclic furano[2,3-d]pyrimidine ribonucleosides were synthesized by Pd(0)- and CuI-catalyzed coupling of 5-iodouridine with terminal alkynes. The treatment of the resulting nucleosides with ammonia or methylamine solution in aqueous alcohol resulted in pyrrolo- and N(7)-methylpyrrolo[2,3-d]pyrimidine nucleosides. 5'-O-Triphosphates of bicyclic nucleosides were obtained by the treatment of the nucleosides with POCl3 in the presence of a "proton sponge." The 5'-O-triphosphates are not substrates for HCV RNA-dependent RNA polymerase, but are effective substrates for HCV RNA helicase/NTPase and did not inhibit ATP hydrolysis. Only 3-(beta-D-ribofuranosyl)-6-decyl-2,3-dihydrofuro-[2,3-d]pyrimidin-2-one showed a moderate anti-HCV activity in the HCV replicon system and efficiently inhibited replication of bovine viral diarrhea virus (BVDV) in KCT-cells, other compounds being inactive. None of the compounds were cytotoxic within the tested range of concentrations.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphatases / antagonists & inhibitors
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Adenosine Triphosphatases / chemistry
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Animals
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Antiviral Agents / chemical synthesis*
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Antiviral Agents / chemistry
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Antiviral Agents / pharmacology
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Cattle
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Cells, Cultured
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Diarrhea Viruses, Bovine Viral / drug effects
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Diarrhea Viruses, Bovine Viral / physiology
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Furans / chemical synthesis*
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Furans / chemistry
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Furans / pharmacology
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Hepacivirus / drug effects
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Humans
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Organophosphates / chemical synthesis*
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Organophosphates / chemistry
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Organophosphates / pharmacology
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Pyrimidine Nucleosides / chemical synthesis*
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Pyrimidine Nucleosides / chemistry
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Pyrimidine Nucleosides / pharmacology
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Pyrroles / chemical synthesis*
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Pyrroles / chemistry
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Pyrroles / pharmacology
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Replicon
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Structure-Activity Relationship
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Viral Nonstructural Proteins / antagonists & inhibitors
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Viral Nonstructural Proteins / chemistry
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Virus Replication / drug effects
Substances
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Antiviral Agents
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Furans
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NS3 protein, hepatitis C virus
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Organophosphates
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Pyrimidine Nucleosides
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Pyrroles
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Viral Nonstructural Proteins
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NS-5 protein, hepatitis C virus
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Adenosine Triphosphatases