The design, synthesis and antiviral evaluation of a series of 5-trimethylsilyl-1-beta-D-(arabinofuranosyl)uracil phosphoramidate ProTides

Antivir Chem Chemother. 2010 Mar 9;20(4):153-60. doi: 10.3851/IMP1476.


Background: Nucleoside analogues always require phosphorylation to be active. This appears to be a particular limitation for uridine-based nucleosides. Our ProTide method allows the direct use of masked membrane-soluble preformed nucleoside phosphates, bypassing the need for the initial phosphorylation step. We herein applied it to some novel 5-trimethylsilyl arabinosyl uridines.

Methods: 5-Trimethylsilyl-1-beta-D-(arabinofuranosyl)uracil was prepared in six steps starting from uridine, and five phosphoramidate ProTide derivatives were synthesized. These compounds were investigated for activity against a range of DNA and RNA viruses, including herpes simplex virus type-1 and type-2, vaccinia virus and HIV.

Results: Overall, these compounds did not show significant antiviral activity against any of the viruses tested.

Conclusions: The inactivity of the ProTides of this nucleoside could correspond with poor ProTide activation in vitro, poor onward metabolism or low activity of the putative monophosphate metabolite.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology
  • Animals
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry*
  • Antiviral Agents / pharmacology*
  • Arabinofuranosyluracil / analogs & derivatives*
  • Arabinofuranosyluracil / chemical synthesis
  • Arabinofuranosyluracil / pharmacology*
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • Cytopathogenic Effect, Viral / drug effects
  • Dogs
  • Fibroblasts / virology
  • Humans
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Phosphoric Acids / chemical synthesis
  • Phosphoric Acids / chemistry
  • Phosphoric Acids / pharmacology
  • Trimethylsilyl Compounds / chemical synthesis
  • Trimethylsilyl Compounds / chemistry
  • Trimethylsilyl Compounds / pharmacology
  • Virus Replication / drug effects


  • Amides
  • Antiviral Agents
  • Phosphoric Acids
  • Trimethylsilyl Compounds
  • Arabinofuranosyluracil
  • phosphoramidic acid