• DOI:10.1021/JM070362I
• Corpus ID: 30478349

First example of phosphoramidate approach applied to a 4'-substituted purine nucleoside (4'-azidoadenosine): conversion of an inactive nucleoside to a submicromolar compound versus hepatitis C virus.

@article{Perrone2007FirstEO,
  title={First example of phosphoramidate approach applied to a 4'-substituted purine nucleoside (4'-azidoadenosine): conversion of an inactive nucleoside to a submicromolar compound versus hepatitis C virus.},
  author={Plinio Perrone and Felice Daverio and Rocco Valente and Sonal Rajyaguru and Joseph A. Martin and Vincent J.-P. Lévêque and Sophie Le Pogam and Isabel Nájera and Klaus Klumpp and David Bernard Smith and Christopher Mcguigan},
  journal={Journal of medicinal chemistry},
  year={2007},
  volume={50 22},
  pages={
          5463-70
        }
}

• Plinio Perrone, F. Daverio, +8 authors C. Mcguigan
• Published 3 October 2007
• Chemistry, Biology
• Journal of medicinal chemistry

We report on the synthesis of the anti hepatitis C virus (HCV) agent 4'-azidoadenosine (1) and the application of the phosphoramidate ProTide technology to this nucleoside. The synthesis of 1 was achieved through an epoxide intermediate followed by regio- and stereoselective ring opening by azidotrimethylsilane in the presence of a Lewis acid. Compound 1 did not inhibit HCV replication in cell culture at concentrations up to 0.1 mM. However, a submicromolar active agent could be derived from 1 by the application of the ProTide technology. All the phosphoramidates prepared were L-alanine derivatives with variations in the aryl moiety and in the ester part of the amino acid. The benzyl ester and the l-naphthyl phosphate (18) had the best activity in replicon assay. Phosphoramidates (18-21) achieved a significant improvement in antiviral potency over the parent nucleoside (1) with no increase in cytotoxicity.