Base-Sensitivity of Arginine Alpha-Ketoamide Inhibitors of Serine Proteases

Martin J. Stoermer; Donmienne Leung; Paul R. Young; David P. Fairlie

doi:10.1071/CH09150

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Base-Sensitivity of Arginine Alpha-Ketoamide Inhibitors of Serine Proteases

Martin J. Stoermer ^A ^C , Donmienne Leung ^A , Paul R. Young ^B and David P. Fairlie ^A

+ Author Affiliations

- Author Affiliations

^A Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, Brisbane, Qld 4072, Australia.

^B School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Qld 4072, Australia.

^C Corresponding author. Email: m.stoermer@imb.uq.edu.au

Australian Journal of Chemistry 62(9) 988-992 https://doi.org/10.1071/CH09150
Submitted: 14 March 2009 Accepted: 9 May 2009 Published: 17 September 2009

Abstract

Serine protease enzymes use a serine hydroxyl group to catalyze hydrolysis of polypeptides. They are important in immunity, blood clotting, digestion, and as therapeutic or diagnostic targets for cancer, diabetes, stroke, inflammatory diseases, and viral infections. Their inhibitors typically possess an electrophile that reacts with the nucleophilic hydroxyl group of the catalytic serine. The α-ketoamide is a valuable electrophile in inhibitor discovery as it permits synthetic elaboration to both sides, unlike other electrophiles. Here we show that an α-ketoamide is unstable above pH 7 when adjacent to the C-terminus of arginine – the guanidine side chain condenses with the α-ketoamide at the keto group rather than the amide carbonyl to form a six-membered hemiaminal rather than a seven-membered lactam.

References

Base-Sensitivity of Arginine Alpha-Ketoamide Inhibitors of Serine Proteases

Abstract

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