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

Mehellou, Youcef; Balzarini, Jan; McGuigan, Christopher

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.