Details

Autor(en) / Beteiligte

• Martínez-Montero, Saúl
• Deleavey, Glen F
• Kulkarni, Anupriya
• Martín-Pintado, Nerea
• Lindovska, Petra
• Thomson, Michael
• González, Carlos
• Götte, Matthias
• Damha, Masad J

Titel

Rigid 2′,4′-Difluororibo­nucleosides: Synthesis, Conformational Analysis, and Incorporation into Nascent RNA by HCV Polymerase

Ist Teil von

• Journal of organic chemistry, 2014-06, Vol.79 (12), p.5627-5635

Ort / Verlag

American Chemical Society

Erscheinungsjahr

2014

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• We 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 “lock” 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 “locked” ribonucleoside mimics that lack a bicyclic ring structure.