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

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• 作者：Sa煤l Mart铆nez-Montero ; Glen F. Deleavey ; Anupriya Kulkarni ; Nerea Mart铆n-Pintado ; Petra Lindovska ; Michael Thomson ; Carlos Gonz谩lez ; Matthias G枚tte ; Masad J. Damha
• 刊名：Journal of Organic Chemistry
• 出版年：2014
• 出版时间：June 20, 2014
• 年：2014
• 卷：79
• 期：12
• 页码：5627-5635
• 全文大小：436K
• 年卷期：v.79,no.12(June 20, 2014)
• ISSN：1520-6904

文摘

We report on the synthesis and conformational properties of 2鈥?deoxy-2鈥?4鈥?difluorouridine (2鈥?4鈥?diF-rU) and cytidine (2鈥?4鈥?diF-rC) nucleosides. NMR analysis and quantum mechanical calculations show that the strong stereoelectronic effects induced by the two fluorines essentially 鈥渓ock鈥?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鈥?4鈥?diF-rU 5鈥?triphosphate (2鈥?4鈥?diF-rUTP) and to link the monophosphate to the RNA primer strand. 2鈥?4鈥?diF-rUTP inhibited RNA synthesis in dinucleotide-primed reactions, although with relatively high half-maximal inhibitory concentrations (IC₅₀ > 50 渭M). 2鈥?4鈥?diF-rU/C represents rare examples of 鈥渓ocked鈥?ribonucleoside mimics that lack a bicyclic ring structure.