Aryloxy Triester Phosphoramidates as Phosphoserine Prodrugs: A Proof of Concept Study |
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Authors: | Dr Ageo Miccoli Dr Binar A Dhiani Dr Peter J Thornton Olivia A Lambourne Dr Edward James Dr Hachemi Kadri Dr Youcef Mehellou |
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Affiliation: | 1. School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3NB UK;2. Technology Solutions GBU, Solvay Solutions, Oldbury, B69 4LN UK;3. Department of Chemistry, Durham University, South Road, Durham, DH1 3LE UK |
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Abstract: | 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. |
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Keywords: | Phosphoserine Phosphoramidate Prodrug 14-3-3 Cancer |
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