Synthesis and anti-HCV activity of β-d-2'-deoxy-2'-α-chloro-2'-β-fluoro and β-d-2'-deoxy-2'-α-bromo-2'-β-fluoro nucleosides and their phosphoramidate prodrugs

  • Bioorg Med Chem. 2019 Feb 15;27(4):664-676. doi: 10.1016/j.bmc.2019.01.005.
Reuben Ovadia  1 ,  Ahmed Khalil  1 ,  Hao Li  1 ,  Coralie De Schutter  1 ,  Seema Mengshetti  1 ,  Shaoman Zhou  1 ,  Leda Bassit  1 ,  Steven J Coats  1 ,  Franck Amblard  1 ,  Raymond F Schinazi  2
Affiliations
  • 1. Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
  • 2. Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: [email protected].
PMID: 30655167 DOI: 10.1016/j.bmc.2019.01.005
Abstract

We report herein the synthesis and evaluation of a series of β-d-2'-deoxy-2'-α-chloro-2'-β-fluoro and β-d-2'-deoxy-2'-α-bromo-2'-β-fluoro nucleosides along with their corresponding phosphoramidate prodrugs. Key intermediates, lactols 11 and 12, were obtained by a diastereoselective fluorination of protected 2-deoxy-2-chloro/bromo-ribonolactones 7 and 8. All synthesized nucleosides and prodrugs were evaluated with a hepatitis C virus (HCV) subgenomic replicon system.

Keywords
Antivirals; Fluorination; Nucleosides; Prodrugs.