The design, synthesis and antiviral evaluation of a series of 5-trimethylsilyl-1-beta-D-(arabinofuranosyl)uracil phosphoramidate ProTides.
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.
Welsh School of Pharmacy, Cardiff University, Cardiff, UK.
Youcef
Y
Mehellou
Jan
J
Balzarini
Christopher
C
McGuigan
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D004285:Dogs; D005347:Fibroblasts / Q000821:virology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010756:Phosphoric Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014297:Trimethylsilyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
D000577:Amides; D000998:Antiviral Agents; D010756:Phosphoric Acids; D014297:Trimethylsilyl Compounds; D001086:Arabinofuranosyluracil; C011067:phosphoramidic acid