Potent and highly selective inhibitors of the proteasome trypsin-like site by incorporation of basic side chain containing amino acid derived sulfonyl fluorides

Artschwager, R., Ward, D. J., Gannon, S., Brouwer, A. J., van de Langemheen, H., Kowalski, H. and Liskamp, R. M.J. (2018) Potent and highly selective inhibitors of the proteasome trypsin-like site by incorporation of basic side chain containing amino acid derived sulfonyl fluorides. Journal of Medicinal Chemistry, 61(12), pp. 5395-5411. (doi:10.1021/acs.jmedchem.8b00685) (PMID:29782167)

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Abstract

A unique category of basic side chain containing amino acid derived sulfonyl fluorides (SFs) has been synthesized for incorporation into new proteasome inhibitors targeting the trypsin-like site of the 20S proteasome. Masking the former α-amino functionality of the amino acid starting derivatives as an azido functionality allowed an elegant conversion to the corresponding amino acid derived sulfonyl fluorides. The inclusion of different SFs at the P1 site of a proteasome inhibitor resulted in 14 different peptidosulfonyl fluorides (PSFs) having a high potency and an excellent selectivity for the proteolytic activity of the β2 subunit over that of the β5 subunit. The results of this study strongly indicate that a free N-terminus of PSFs inhibitors is crucial for high selectivity toward the trypsin-like site of the 20S proteasome. Nevertheless, all compounds are slightly more selective for inhibition of the constitutive over the immunoproteasome.

Item Type:Articles
Additional Information:This research was funded by the University of Glasgow.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Liskamp, Professor Robert and Ward, Mr David and Van De Langemheen, Mr Helmus and Artschwager, Raik and Gannon, Dr Susan
Authors: Artschwager, R., Ward, D. J., Gannon, S., Brouwer, A. J., van de Langemheen, H., Kowalski, H., and Liskamp, R. M.J.
College/School:College of Science and Engineering > School of Chemistry
Journal Name:Journal of Medicinal Chemistry
Publisher:American Chemical Society
ISSN:0022-2623
ISSN (Online):1520-4804
Published Online:21 May 2018
Copyright Holders:Copyright © 2018 American Chemical Society
First Published:First published in Journal of Medicinal Chemistry 61(12): 5395-5411
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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