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Aryloxy triester phosphoramidates as phosphoserine prodrugs: a proof of concept study

Miccoli, Ageo, Dhiani, Binar A., Thornton, Peter J., Lambourne, Olivia A., James, Edward, Kadri, Hachemi and Mehellou, Youcef ORCID: 2020. Aryloxy triester phosphoramidates as phosphoserine prodrugs: a proof of concept study. ChemMedChem 15 (8) , pp. 671-674. 10.1002/cmdc.202000034

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The specific targeting of protein‐protein interactions by phosphoserine‐containing small molecules has been scarce due to the dephosphorylation of phosphoserine and its charged nature at physiological pH, which hinder its uptake into cells. To address these issues, we herein report the synthesis of phosphoserine aryloxy triester phosphoramidates as phosphoserine prodrugs that are enzymatically metabolized to release phosphoserine. This phosphoserine‐masking approach was applied to a phosphoserine‐containing inhibitor of 14‐3‐3 dimerization, and the generated prodrugs exhibited improved pharmacological activity. Collectively, this provided a proof of concept that the masking of phosphoserine with biocleavable aryloxy triester phosphoramidate masking groups is a viable intracellular delivery system for phosphoserine‐containing molecules. Ultimately, this will facilitate the discovery of phosphoserine‐containing small‐molecule therapeutics.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Publisher: Wiley
ISSN: 1860-7179
Date of First Compliant Deposit: 8 April 2020
Date of Acceptance: 2 March 2020
Last Modified: 20 Feb 2024 17:26

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