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Discovery and Synthesis of C‑Nucleosides as Potential New Anti-HCV Agents

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journal contribution
posted on 12.06.2014, 00:00 by Alistair G. Draffan, Barbara Frey, Brett Pool, Carlie Gannon, Edward M. Tyndall, Michael Lilly, Paula Francom, Richard Hufton, Rosliana Halim, Saba Jahangiri, Silas Bond, Van T. T. Nguyen, Tyrone P. Jeynes, Veronika Wirth, Angela Luttick, Danielle Tilmanis, Jesse D. Thomas, Melinda Pryor, Kate Porter, Craig J. Morton, Bo Lin, Jianmin Duan, George Kukolj, Bruno Simoneau, Ginette McKercher, Lisette Lagacé, Ma’an Amad, Richard C. Bethell, Simon P. Tucker
Nucleoside analogues have long been recognized as prospects for the discovery of direct acting antivirals (DAAs) to treat hepatitis C virus because they have generally exhibited cross-genotype activity and a high barrier to resistance. C-Nucleosides have the potential for improved metabolism and pharmacokinetic properties over their N-nucleoside counterparts due to the presence of a strong carbon–carbon glycosidic bond and a non-natural heterocyclic base. Three 2′CMe-C-adenosine analogues and two 2′CMe-guanosine analogues were synthesized and evaluated for their anti-HCV efficacy. The nucleotide triphosphates of four of these analogues were found to inhibit the NS5B polymerase, and adenosine analogue 1 was discovered to have excellent pharmacokinetic properties demonstrating the potential of this drug class.

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