[Synthesis and biological properties of pyrimidine 4'-fluoro nucleosides and 4'-fluoro uridine 5'-O-triphospate].
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).
Ivanov
M A
MA
Liudva
G S
GS
Mukovnia
A V
AV
Kochetkov
S N
SN
Tunitskaia
V L
VL
Aleksnadrova
L A
LA
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry; D016174:Hepacivirus / Q000201:enzymology*; D006845:Hydrocarbons, Fluorinated; D011684:Purine Nucleosides / Q000138:chemical synthesis / Q000737:chemistry; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014544:Uridine Triphosphate / Q000138:chemical synthesis / Q000737:chemistry; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D006845:Hydrocarbons, Fluorinated; D011684:Purine Nucleosides; D012324:RNA-Dependent RNA Polymerase; D014544:Uridine Triphosphate; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases