1. Academic Validation
  2. Synthesis and antiviral activity of 2'-deoxy-2'-fluoro-2'-C-methyl-7-deazapurine nucleosides, their phosphoramidate prodrugs and 5'-triphosphates

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

  • Bioorg Med Chem Lett. 2011 Dec 1;21(23):7094-8. doi: 10.1016/j.bmcl.2011.09.089.
Junxing Shi 1 Longhu Zhou Hongwang Zhang Tamara R McBrayer Mervi A Detorio Melissa Johns Leda Bassit Megan H Powdrill Tony Whitaker Steven J Coats Matthias Götte Raymond F Schinazi
Affiliations

Affiliation

  • 1 RFS Pharma, LLC, 1860 Montreal Road, Tucker, GA 30084, USA.
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 (EC(50)=0.71±0.25 μM; EC(90)=9.5±3.3 μM) with no observed cytotoxicity up to 100 μM in four different cell lines.

Figures