Synthesis and biological evaluation of 6-substituted-5-fluorouridine ProTides

Slusarczyk, Magdalena ORCID: https://orcid.org/0000-0002-4707-7190, Ferla, Salvatore ORCID: https://orcid.org/0000-0002-5918-9237, Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419 and McGuigan, Christopher 2018. Synthesis and biological evaluation of 6-substituted-5-fluorouridine ProTides. Bioorganic and Medicinal Chemistry 26 (3) , pp. 551-565. 10.1016/j.bmc.2017.11.037

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Abstract

A new family of thirteen phosphoramidate prodrugs (ProTides) of different 6-substituted-5-fluorouridine nucleoside analogues were synthesized and evaluated as potential anticancer agents. In addition, antiviral activity against Chikungunya (CHIKV) virus was evaluated using a cytopathic effect inhibition assay. Although a carboxypeptidase Y assay supported a putative mechanism of activation of ProTides built on 5-fluorouridine with such C6-modifications, the Hint docking studies revealed a compromised substrate-activity for the Hint phosphoramidase-type enzyme that is likely responsible for phosphoramidate bioactivation through P-N bond cleavage and free nucleoside 5’-monophosphate delivery. Our observations may support and explain to some extent the poor in vitro biological activity generally demonstrated by the series of 6-substituted-5-fluorouridine phosphoramidates (ProTides) and will be of guidance for the design of novel phosphoramidate prodrugs.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
Publisher:	Elsevier
ISSN:	0968-0896
Date of First Compliant Deposit:	8 December 2017
Date of Acceptance:	23 November 2017
Last Modified:	12 Nov 2024 09:30
URI:	https://orca.cardiff.ac.uk/id/eprint/107477

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