Aryloxy Triester Phosphoramidates as Phosphoserine Prodrugs: A Proof of Concept Study,ChemMedChem

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Aryloxy Triester Phosphoramidates as Phosphoserine Prodrugs: A Proof of Concept Study
ChemMedChem ( IF 3.6 ) Pub Date : 2020-03-26 , DOI: 10.1002/cmdc.202000034
Ageo Miccoli ₁ , Binar A. Dhiani ₁ , Peter J. Thornton ₂ , Olivia A. Lambourne ₁ , Edward James ₁ , Hachemi Kadri ₃ , Youcef Mehellou ₁

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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.

中文翻译：

芳氧基三酯磷酸氨基磷酸酯作为磷酸丝氨酸的前药：概念研究的证明。

由于磷酸丝氨酸的去磷酸化及其在生理pH下的带电性质，阻碍了其被吸收到细胞中，因此含磷酸丝氨酸的小分子对蛋白质-蛋白质相互作用的特异性靶向一直很少。为了解决这些问题，我们在本文中报道了磷酸丝氨酸芳氧基三酯氨基磷酸酯作为磷酸丝氨酸前药的合成，其被酶促代谢以释放磷酸丝氨酸。这种磷酸丝氨酸掩蔽方法被应用于含磷酸丝氨酸的14-3-3二聚化抑制剂，并且生成的前药显示出改善的药理活性。总的来说，这提供了一个概念证明，即利用可生物裂解的芳氧基三酯氨基磷酸酯掩蔽基团掩蔽磷酸丝氨酸对于含磷酸丝氨酸的分子而言是一种可行的细胞内递送系统。最终，

更新日期：2020-04-22

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