Synthesis and antiviral activity of 2′-deoxy-2′-fluoro-2′-C-methyl-7-deazapurine nucleosides, their phosphoramidate prodrugs and 5′-triphosphates

• Authors: Junxing Shi, RFS Pharma, LLC; Longhu Zhou, Emory University; HongWang Zhang, Emory University; Tamara R. McBrayer, RFS Pharma, LLC; Mervi Acuzar Detorio, Emory University; Melissa Johns, Emory University; Leda C. Bassit, Emory University; Megan H. Powdrill, McGill University; Tony Whitaker, RFS Pharma, LLC; Steven J. Coats, RFS Pharma, LLC; Matthias Götte, McGill University; Raymond F Schinazi, Emory University
• Journal Title: Bioorganic and Medicinal Chemistry Letters
• Volume: Volume 21, Number 23
• Publisher: Elsevier | 2011-12-01, Pages 7094-7098
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1016/j.bmcl.2011.09.089
• Subjects: Chemistry, Pharmaceutical
• Keywords: HCV; antiviral; 7-deazapurine; nucleoside; nucleotide; prodrug; Mitsunobu

Abstract

Thirty novel α- and β-D-2′-deoxy-2′-fluoro-2′-C-methyl-7-deazapurine nucleoside analogs were synthesized and evaluated for in vitro antiviral activity. Several α- and β-7-deazapurine nucleoside analogs exhibited modest anti-HCV activity and cytotoxicity. Four synthesized 7-deazapurine nucleoside phosphoramidate prodrugs (18–21) showed no anti-HCV activity, whereas the nucleoside triphosphates (22–24) demonstrated potent inhibitory effects against both wild-type and S282T mutant HCV polymerases. Cellular pharmacology studies in Huh-7 cells revealed that the 5′-triphosphates were not formed at significant levels from either the nucleoside or the phosphoramidate prodrugs, indicating that insufficient phosphorylation was responsible for the lack of anti-HCV activity. Evaluation of anti-HIV-1 activity revealed that an unusual α-form of 7-carbomethoxyvinyl substituted nucleoside (10) had good anti-HIV-1 activity (EC50 = 0.71 ± 0.25 μM; EC90 = 9.5 ± 3.3 μM) with no observed cytotoxicity up to 100 μM in four different cell lines.