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

Slusarczyk, Magdalena, Ferla, Salvatore, Brancale, Andrea 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: 28 Jul 2019 21:24
URI: http://orca.cf.ac.uk/id/eprint/107477

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