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Title

Rigid 2′,4′-difluororibonucleosides: Synthesis, conformational analysis, and incorporation into nascent RNA by HCV polymerase

AuthorsMartínez-Montero, S.; Deleavey, G.F.; Kulkarni, A.; Martín-Pintado, N. ; Lindovska, P.; Thomson, M.; González, Carlos ; Götte, M.; Damha, M.J.
Issue Date2014
PublisherAmerican Chemical Society
CitationJournal of Organic Chemistry 79: 5627- 5635 (2014)
AbstractWe report on the synthesis and conformational properties of 2′-deoxy-2′,4′-difluorouridine (2′,4′-diF-rU) and cytidine (2′,4′-diF-rC) nucleosides. NMR analysis and quantum mechanical calculations show that the strong stereoelectronic effects induced by the two fluorines essentially ́locḱ the conformation of the sugar in the North region of the pseudorotational cycle. Our studies also demonstrate that NS5B HCV RNA polymerase was able to accommodate 2′,4′-diF-rU 5′-triphosphate (2′,4′-diF-rUTP) and to link the monophosphate to the RNA primer strand. 2′,4′-diF-rUTP inhibited RNA synthesis in dinucleotide-primed reactions, although with relatively high half-maximal inhibitory concentrations (IC50 > 50 μM). 2′,4′- diF-rU/C represents rare examples of ́locked́ ribonucleoside mimics that lack a bicyclic ring structure. © 2014 American Chemical Society.
URIhttp://hdl.handle.net/10261/167827
Identifiersdoi: 10.1021/jo500794v
issn: 1520-6904
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