[Synthesis and biological properties of pyrimidine 4'-fluoro nucleosides and 4'-fluoro uridine 5'-O-triphospate]

Bioorg Khim. 2010 Jul-Aug;36(4):526-34. doi: 10.1134/s1068162010040072.
[Article in Russian]

Abstract

4'- Fluoro-2',3'-O-isopropylidenecytidine was synthesized via interaction of 5'-O-acetyl-4'-fluoro-2',3'-O-isopropylideneuridine with triazole and 4-chlorophenyl dichlorophosphate followed by ammonolysis. Treatment of 5'-O-acetyl-4'-fluoro-2',3'-O-isopropylidenecytidine with hydroxylamine resulted in 5'-O-acetyl-4'-fluoro-2',3'-O-isopropylidene-N(4)-hydroxycytidine. Subsequent removal of 2',3'-O-isopropylidene groups gave 5'-O-acetyl derivatives of 4'-fluorouridine, 4'-fluorocytidine and 4'-fluoro-N(4)-hydroxycytidine. 5'-O-Triphosphate of 4'-fluorouridine was obtained in three steps starting from 4'-fluoro-2',3'-O-isopropylideneuridine. The 4'-fluoro uridine 5'-O-triphospate was found to be an effective inhibitor of HCV RNA-dependent RNA polymerase, substrate for NTPase reaction, catalyzed by protein NS3 HCV (a rate of the analogue hydrolysis was similar to that of ATP) and an activator for helicase reaction (with an efficacy only three fold lower than that of ATP).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Hepacivirus / enzymology*
  • Hydrocarbons, Fluorinated*
  • Purine Nucleosides* / chemical synthesis
  • Purine Nucleosides* / chemistry
  • RNA-Dependent RNA Polymerase / antagonists & inhibitors*
  • RNA-Dependent RNA Polymerase / chemistry
  • Uridine Triphosphate* / chemical synthesis
  • Uridine Triphosphate* / chemistry
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / chemistry

Substances

  • Antiviral Agents
  • Hydrocarbons, Fluorinated
  • NS3 protein, hepatitis C virus
  • Purine Nucleosides
  • Viral Nonstructural Proteins
  • RNA-Dependent RNA Polymerase
  • Uridine Triphosphate