Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 145, Issue -, Pages 570-587Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2018.01.013
Keywords
Proteasome inhibitors; Immunoproteasome; Constitutive proteasome; 3-HydroxyOxindolylalanine derivatives; Tryptophan oxidation
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Funding
- Centre National de la Recherche Scientifique (CNRS)
- University of Rennes 1
- Universite Pierre et Marie Curie
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Starting from the X-ray structure of our previous tripeptidic linear mimics of TMC-95A in complex with yeast 20S proteasome, we introduced new structural features to induce a differential inhibition between human constitutive and immunoproteasome 20S particles. Libraries of 24 tripeptidic and 6 dipeptidic derivatives were synthesized. The optimized preparation of 3-hydroxyoxindolyl alanine residues from tryptophan and their incorporation in peptides were described. Several potent inhibitors of human constitutive proteasome and immunoproteasome acting at the nanomolar level (IC50 = 7.1 nM against the chymotrypsin-like activity for the best inhibitor) were obtained. A cytotoxic effect at the submicromolar level was observed against 6 human cancer cell lines. (C) 2018 Elsevier Masson SAS. All rights reserved.
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