Synthesis and biological properties of pyrimidine 4′-fluoronucleosides and 4′-fluorouridine 5′-O-triphosphate

4′-Fluoro-2′,3′-O-isopropylidenecytidine was synthesized by the treatment of 5′-O-acetyl-4′-fluoro-2′,3′-O-isopropylideneuridine with triazole and 4-chlorophenyl dichlorophosphate followed by ammonolysis. The interaction of 4′-fluoro-2′,3′-O-isopropylidenecytidine with hydroxylamine resulted in 4′-f...

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Bibliographic Details
Published in:	Russian journal of bioorganic chemistry Vol. 36; no. 4; pp. 488 - 496
Main Authors:	Ivanov, M. A, Ludva, G. S, Mukovnya, A. V, Kochetkov, S. N, Tunitskaya, V. L, Alexandrova, L. A
Format:	Journal Article
Language:	English
Published:	Dordrecht Dordrecht : SP MAIK Nauka/Interperiodica 01-07-2010 SP MAIK Nauka/Interperiodica
Subjects:	4′-fluoropyrimidine ribonucleosides Biochemistry Biomedical and Life Sciences Biomedicine Bioorganic Chemistry HCV RNA helicase/NTPase HCV RNA-dependent RNA polymerase Hepatitis C virus Life Sciences nucleoside 5′-O-triphosphates nucleosides Organic Chemistry hepatitis C virus nucleosides HCV RNA-dependent RNA polymerase 4′-fluoropyrimidine ribonucleosides nucleoside 5′-O-triphosphates HCV RNA helicase/NTPase
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Summary:	4′-Fluoro-2′,3′-O-isopropylidenecytidine was synthesized by the treatment of 5′-O-acetyl-4′-fluoro-2′,3′-O-isopropylideneuridine with triazole and 4-chlorophenyl dichlorophosphate followed by ammonolysis. The interaction of 4′-fluoro-2′,3′-O-isopropylidenecytidine with hydroxylamine resulted in 4′-fluoro-2′,3′-O-isopropylidene-5′-O-acetyl-N ⁴-hydroxycytidine. The removal of the 2′,3′-O-isopropylidene groups led to acetyl derivatives of 4′-fluorouridine, 4′-fluorocytidine, and 4′-fluoro-N ⁴-hydroxycytidine. 4′-Fluorouridine 5′-O-triphosphate was obtained in three steps starting from 4′-fluoro-2′,3′-O-isopropylideneuridine. 4′-Fluorouridine 5′-O-triphosphate was shown to be an effective inhibitor of HCV RNA-dependent RNA polymerase and a substrate for the NTPase reaction catalyzed by the HCV NS3 protein, the hydrolysis rate being similar to that of ATP. It could also activate a helicase reaction with an efficacy of only threefold lower than that for ATP.
Bibliography:	http://dx.doi.org/10.1134/S1068162010040072 ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	1068-1620 1608-330X
DOI:	10.1134/S1068162010040072