2. Academic Validation
  3. Synthesis and anti-HCV activity of a series of β-d-2'-deoxy-2'-dibromo nucleosides and their corresponding phosphoramidate prodrugs

Synthesis and anti-HCV activity of a series of β-d-2'-deoxy-2'-dibromo nucleosides and their corresponding phosphoramidate prodrugs

  • Bioorg Med Chem Lett. 2017 Dec 1;27(23):5296-5299. doi: 10.1016/j.bmcl.2017.10.024.
Zhe Chen 1,  Bryan D Cox 1,  Ethel C Garnier-Amblard 2,  Tamara R McBrayer 2,  Steven J Coats 2,  Raymond F Schinazi 3,  Franck Amblard 4
Affiliations

Affiliations

  • 1 Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University, School of Medicine, Atlanta, GA 30322, United States.
  • 2 Cocrystal Pharma, Inc., Tucker, GA 30084, United States.
  • 3 Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University, School of Medicine, Atlanta, GA 30322, United States. Electronic address: rschina@emory.edu.
  • 4 Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University, School of Medicine, Atlanta, GA 30322, United States. Electronic address: famblar@emory.edu.
PMID: 29066308 DOI: 10.1016/j.bmcl.2017.10.024
Abstract

Several β-d-2'-deoxy-2'-substituted nucleoside analogs have displayed potent and selective anti-HCV activities and some of them have reached human clinical trials. In that regard, we report herein the synthesis of a series of 2'-deoxy,2'-dibromo substituted U, C, G and A nucleosides 10a-d and their corresponding phosphoramidate prodrugs 13a-d. The synthesized nucleosides 10a-d and prodrugs 13a-d were evaluated for their inhibitory activity against HCV as well as cellular toxicity. The results showed that the most potent compound was prodrug 13a, which exhibited micromolar inhibitory activity (EC50 = 1.5 ± 0.8 µM) with no observed toxicity. In addition, molecular modeling and free energy perturbation calculations for the 5'-triphosphate formed from 13a and related 2'-modified nucleotides are discussed.

Keywords

Hepatitis C virus; Nucleoside; Prodrug; Synthesis.

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