Aryloxy Triester Phosphoramidates as Phosphoserine Prodrugs‐ A Proof of Concept Study

Miccoli, Ageo; Dhiani, Binar; Thornton, Peter; Lambourne, Olivia; James, Edward; Kadri, Hachemi; Mehellou, Youcef

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 hinders its uptake into cells. To address these issues, we herein report the synthesis of phosphoserine aryloxy triester phosphoramidates as phosphoserine prodrugs, which 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 of the masking of phosphoserine with biocleavable aryloxy triester phosphoramidate masking groups as a viable intracellular delivery system for phosphoserine‐containing molecules. Ultimately, this will facilitate the discovery of phosphoserine‐containing small molecule therapeutics.

Citation

Miccoli, A., Dhiani, B., Thornton, P., Lambourne, O., James, E., Kadri, H., & Mehellou, Y. (2020). Aryloxy Triester Phosphoramidates as Phosphoserine Prodrugs‐ A Proof of Concept Study. ChemMedChem, 15(8), 671-674. https://doi.org/10.1002/cmdc.202000034

• Journal Article Type: Article
• Acceptance Date: Mar 11, 2020
• Online Publication Date: Mar 26, 2020
• Publication Date: Apr 20, 2020
• Deposit Date: Mar 13, 2020
• Publicly Available Date: Mar 26, 2021
• Journal: ChemMedChem
• Print ISSN: 1860-7179
• Electronic ISSN: 1860-7187
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 15
• Issue: 8
• Pages: 671-674
• DOI: https://doi.org/10.1002/cmdc.202000034