Aryloxy phosphoramidate triesters: a technology for delivering monophosphorylated nucleosides and sugars into cells

ChemMedChem. 2009 Nov;4(11):1779-91. doi: 10.1002/cmdc.200900289.


Prodrug technologies aimed at delivering nucleoside monophosphates into cells (protides) have proved to be effective in improving the therapeutic potential of antiviral and anticancer nucleosides. In these cases, the nucleoside monophosphates are delivered into the cell, where they may then be further converted (phosphorylated) to their active species. Herein, we describe one of these technologies developed in our laboratories, known as the phosphoramidate protide method. In this approach, the charges of the phosphate group are fully masked to provide efficient passive cell-membrane penetration. Upon entering the cell, the masking groups are enzymatically cleaved to release the phosphorylated biomolecule. The application of this technology to various therapeutic nucleosides has resulted in improved antiviral and anticancer activities, and in some cases it has transformed inactive nucleosides to active ones. Additionally, the phosphoramidate technology has also been applied to numerous antiviral nucleoside phosphonates, and has resulted in at least three phosphoramidate-based nucleotides progressing to clinical investigations. Furthermore, the phosphoramidate technology has been recently applied to sugars (mainly glucosamine) in order to improve their therapeutic potential. The development of the phosphoramidate technology, mechanism of action and the application of the technology to various monophosphorylated nucleosides and sugars will be reviewed.

Publication types

  • Review

MeSH terms

  • Amides / chemistry*
  • Amides / pharmacology
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • Carbohydrates / chemistry*
  • Carbohydrates / pharmacology
  • Cell Line, Tumor
  • Drug Carriers
  • Humans
  • Nucleosides / chemistry*
  • Nucleosides / pharmacology
  • Phosphoric Acids / chemistry*
  • Phosphoric Acids / pharmacology


  • Amides
  • Anti-HIV Agents
  • Antineoplastic Agents
  • Antiviral Agents
  • Carbohydrates
  • Drug Carriers
  • Nucleosides
  • Phosphoric Acids
  • phosphoramidic acid