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

• Type of Material: Article
• Authors: Zhe Chen, Emory University; Bryan Cox, Emory University; Ethel C. Garnier-Amblard, Cocrystal Pharma Inc; Tamara R. McBrayer, Cocrystal Pharma Inc; Steven Coats, Emory University; Raymond Schinazi, Emory University; Franck Amblard, Emory University
• Language: English
• Date: 2017-12-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Elsevier Ltd
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bmcl.2017.10.024
• Title of Journal or Parent Work: Bioorganic and Medicinal Chemistry Letters
• ISSN: 0960-894X
• Volume: 27
• Issue: 23
• Start Page: 5296
• End Page: 5299
• Grant/Funding Information: This work was supported in part by NIH grant 5P30-AI-50409 (CFAR).; Emory received no funding from Cocrystal Pharma, Inc. to perform this work and vice versa.
• Keywords: HEPATITIS-C; Life Sciences & Biomedicine; Nucleoside; Prodrug; Chemistry; Science & Technology; HUMAN-IMMUNODEFICIENCY-VIRUS; Synthesis; DISCOVERY; Chemistry, Organic; Chemistry, Medicinal; Pharmacology & Pharmacy; Hepatitis C virus; REPLICATION; Physical Sciences; CULTURE
• Research Categories: Chemistry, Biochemistry; Chemistry, Organic

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.