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.
- 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: [email protected].
- 4. Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University, School of Medicine, Atlanta, GA 30322, United States. Electronic address: [email protected].
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.