An investigation into the anti-HIV activity of 2',3'-didehydro-2',3'-dideoxyuridine (d4U) and 2',3'-dideoxyuridine (ddU) phosphoramidate 'ProTide' derivatives

Org Biomol Chem. 2009 Jun 21;7(12):2548-53. doi: 10.1039/b904276h. Epub 2009 Apr 30.


As part of our studies on the anti-HIV activities of 2',3'-didehydro-2',3'-dideoxyuridine (d4U), 2',3'-dideoxyuridine (ddU) and their 'ProTides', we have prepared and evaluated the anti-HIV activity of a range of d4U and ddU aryl triester phosphoramidates. Besides elucidating SAR characteristics, we performed molecular modelling studies on both d4U and ddU in order to probe the first phosphorylation step required for the activation of these two nucleoside analogues. Overall, the application of the phosphoramidate approach turned the inactive ddU to a moderately active anti-HIV agent, while this was not the case with d4U. Enzymatic assays investigating the metabolism of d4U phosphoramidates revealed an efficient cleavage of the phosphoramidate motif to release the d4U monophosphate. Thus, a poor second and/or third phosphorylation step may be the most likely reason for the virtual lack of anti-HIV activity in this case.

MeSH terms

  • Amides / chemistry*
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / metabolism
  • Anti-HIV Agents / pharmacology*
  • Cathepsins / metabolism
  • Dideoxynucleosides / chemistry*
  • Dideoxynucleosides / metabolism
  • Dideoxynucleosides / pharmacology*
  • HIV / drug effects*
  • Humans
  • Inhibitory Concentration 50
  • Models, Molecular
  • Molecular Conformation
  • Organophosphorus Compounds / chemistry*
  • Organophosphorus Compounds / metabolism
  • Organophosphorus Compounds / pharmacology*
  • Phosphoric Acids / chemistry*
  • Triazoles / chemistry*
  • Triazoles / metabolism
  • Triazoles / pharmacology*


  • Amides
  • Anti-HIV Agents
  • Dideoxynucleosides
  • Organophosphorus Compounds
  • Phosphoric Acids
  • Triazoles
  • diglycidyl-(3-(3,3-bisphosphono-3-hydroxypropylamino)-2-hydroxypropyl)urazol
  • 2',3'-didehydro-2',3'-dideoxyuridine
  • phosphoramidic acid
  • Cathepsins