α- and β-hydrazino acid-based pseudopeptides inhibit the chymotrypsin-like activity of the eukaryotic 20S proteasome

• Published in: European journal of medicinal chemistry Vol. 70; pp. 505 - 524
• Main Authors: Bordessa, Andrea, Keita, Massaba, Maréchal, Xavier, Formicola, Lucia, Lagarde, Nathalie, Rodrigo, Jordi, Bernadat, Guillaume, Bauvais, Cyril, Soulier, Jean-Louis, Dufau, Laure, Milcent, Thierry, Crousse, Benoit, Reboud-Ravaux, Michèle, Ongeri, Sandrine
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 01.12.2013; Elsevier
• Subjects: Animals; Chemistry, Medicinal; Chymotrypsin; Chymotrypsin - antagonists & inhibitors; Chymotrypsin - metabolism; Dose-Response Relationship, Drug; Fluorine; Hydrazines - chemical synthesis; Hydrazines - chemistry; Hydrazines - pharmacology; Hydrazino acid; Life Sciences & Biomedicine; Models, Molecular; Molecular Structure; Peptides - chemical synthesis; Peptides - chemistry; Peptides - pharmacology; Pharmacology & Pharmacy; Proteasome inhibitors; Proteasome Inhibitors - chemical synthesis; Proteasome Inhibitors - chemistry; Proteasome Inhibitors - pharmacology; Pseudopeptide; Rabbits; Science & Technology; Structure-Activity Relationship; Trifluoromethyl; Trifluoromethyl; Chymotrypsin; Hydrazino acid; Fluorine; Proteasome inhibitors; Pseudopeptide; MULTIPLE-MYELOMA; DESIGN; DOCKING; BORTEZOMIB; PEPTIDE; ANGSTROM RESOLUTION; POTENT; TMC-95A; DERIVATIVES; AZAPEPTOIDS
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2013.09.059

We describe the synthesis of a library of new pseudopeptides and their inhibitory activity of the rabbit 20S proteasome chymotrypsin-like (ChT-L) activity. We replaced a natural α-amino acid by an α- or a β-hydrazino acid and obtained inhibitors of proteasome up to a submicromolar range (0.7 μM for molecule 24b). Structural variations influenced the inhibition of the ChT-L activity. Models of inhibitor/20S proteasome complexes corroborated the inhibition efficacies obtained by kinetic studies. [Display omitted] •A novel class of non covalent proteasome inhibitors is described.•A natural α-amino acid was replaced by an α- or a β-hydrazino acid.•A CF3-β-hydrazino acid scaffold was introduced.•Inhibition of the proteasome chymotrypsin-like activity up to a submicromolar range.•Models of the binding mode of inhibitors to ChT-L subunit.