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UNIT 15.5 Synthesis of Phosphoramidate Prodrugs: ProTide Approach

  1. Michaela Serpi,
  2. Karolina Madela,
  3. Fabrizio Pertusati,
  4. Magdalena Slusarczyk

Published Online: 1 JUN 2013

DOI: 10.1002/0471142700.nc1505s53

Current Protocols in Nucleic Acid Chemistry

Current Protocols in Nucleic Acid Chemistry

How to Cite

Serpi, M., Madela, K., Pertusati, F. and Slusarczyk, M. 2013. Synthesis of Phosphoramidate Prodrugs: ProTide Approach. Current Protocols in Nucleic Acid Chemistry. 53:15.5:15.5.1–15.5.15.

Author Information

  1. School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, United Kingdom

Publication History

  1. Published Online: 1 JUN 2013

Abstract

The ProTide (pronucleotide) approach is a prodrug strategy elaborated to deliver nucleoside monophosphate into the cell, circumventing the first and inefficient rate-limiting phosphorylation step of nucleosides and improving the cellular penetration of nucleotides. The ProTide of a nucleoside phosphate is a phosphoramidate prodrug consisting of an amino acid ester promoiety linked via P-N bond to a nucleoside aryl phosphate. Such prodrugs have increased lipophilicity and thus are capable of altering cell and tissue distribution. The ProTide technology was successfully and extensively applied to a wide variety of nucleoside phosphates, endowed with antiviral and anticancer activity. This unit describes two different synthetic strategies allowing the preparation of phosphoramidates of 6-O-methyl-2′−β-C-methylguanosine as model compounds for nucleosides having only the 5′-OH as reactive hydroxyl group, and phosphoramidates of 2′−β-d-arabinouridine (AraU) as model compounds for nucleosides containing two or more reactive hydroxyl groups. Curr. Protoc. Nucleic Acid Chem. 53:15.5.1-15.5.15. © 2013 by John Wiley & Sons, Inc.

Keywords:

  • ProTide;
  • phosphoramidate nucleoside;
  • nucleotide;
  • antiviral and anticancer pro-drugs