Bicyclic and Tricyclic "Expanded" Nucleobase Analogues of Sofosbuvir: New Scaffolds for Hepatitis C Therapies.
Given the impressive success of Gilead's Sofosbuvir, many laboratories, including ours, have explored the unique 2'-sugar modification (2'-Me, 2'-F) of nucleoside analogues in the hopes of exploiting the biological activity that this unique modification has imparted to the nucleoside scaffold. In that regard, we have combined our tricyclic "expanded" purine base motif with the 2'-Me, 2'-F sugar modification. Although the synthesis of these complex molecules proved to be nontrivial, with the best results coming from a linear approach, the overall strategy resulted in highly promising biological results for several of the target compounds, including their corresponding McGuigan ProTides. Modest activity against HCV was observed with inhibitory concentrations of as low as 20 μM.
Department of Chemistry & Biochemistry, University of Maryland, Baltimore County , Baltimore, Maryland 21250, United States.
Zhe
Z
Chen
Rega Institute, University of Leuven (KU Leuven) , Leuven, Belgium.
Dirk
D
Jochmans
Department of Chemistry & Biochemistry, University of Maryland, Baltimore County , Baltimore, Maryland 21250, United States.
Therese
T
Ku
Rega Institute, University of Leuven (KU Leuven) , Leuven, Belgium.
Jan
J
Paeshuyse
Rega Institute, University of Leuven (KU Leuven) , Leuven, Belgium.
Johan
J
Neyts
Department of Chemistry & Biochemistry, University of Maryland, Baltimore County , Baltimore, Maryland 21250, United States.
Katherine L
KL
Seley-Radtke
Huh 5.2; Sofosbuvir; antireplicon effect; antiviral; hepatitis C; luminescence; nucleoside scaffold; purines