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

Mehellou, Youcef ORCID: https://orcid.org/0000-0001-5720-8513, Balzarini, Jan and McGuigan, Christopher ORCID: https://orcid.org/0000-0001-8409-710X 2010. The design, synthesis and antiviral evaluation of a series of 5-trimethylsilyl-1-β-D-(arabinofuranosyl)uracil phosphoramidate ProTides. Antiviral Chemistry & Chemotherapy 20 (4) , pp. 153-160. 10.3851/IMP1476

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Abstract

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-β-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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy Systems Immunity Research Institute (SIURI)
Subjects:	R Medicine > RS Pharmacy and materia medica
ISSN:	09563202
Last Modified:	17 Oct 2022 10:08
URI:	https://orca.cardiff.ac.uk/id/eprint/6993

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