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The phosphoramidate ProTide approach greatly enhances the activity of beta-2 '-C-methylguanosine against hepatitis C virus

McGuigan, Christopher, Perrone, Plinio, Madela, Karolina and Neyts, Johan 2009. The phosphoramidate ProTide approach greatly enhances the activity of beta-2 '-C-methylguanosine against hepatitis C virus. Biorganic and Medicinal Chemistry Letters 19 (15) , pp. 4316-4320. 10.1016/j.bmcl.2009.05.122

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Abstract

β-2′-C-Methyl purines (1, 2) are known inhibitors of hepatitis C virus (HCV). We herein report the synthesis, biological and enzymatic evaluation of their 5′-phosphoramidate ProTides. Described herein are seven l-alanine phosphoramidate derivatives with variations to the amino acid ester. The 1-naphthyl phosphoramidate of β-2′-methylguanosine containing the benzyl ester (20) was the most active at 0.12 μM, an 84-fold of increase in activity compared to the parent nucleoside (2) with no increase of cytotoxicity. The carboxypeptidase mediated hydrolysis of several ProTides showed a predictive correlation with their activity versus HCV in replicon.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > RS Pharmacy and materia medica
Uncontrolled Keywords: HCV; Protide; Phosphoramidate; Nucleoside; Nucleotide; Antiviral; Pro-drug
Publisher: Elsevier
ISSN: 0960-894X
Last Modified: 18 Oct 2017 13:14
URI: http://orca.cf.ac.uk/id/eprint/6645

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