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

Eur J Med Chem. 2013:70:505-24. doi: 10.1016/j.ejmech.2013.09.059. Epub 2013 Oct 17.

Abstract

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.

Keywords: Chymotrypsin; Fluorine; Hydrazino acid; Proteasome inhibitors; Pseudopeptide; Trifluoromethyl.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chymotrypsin / antagonists & inhibitors*
  • Chymotrypsin / metabolism
  • Dose-Response Relationship, Drug
  • Hydrazines / chemical synthesis
  • Hydrazines / chemistry
  • Hydrazines / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Peptides / chemical synthesis
  • Peptides / chemistry
  • Peptides / pharmacology*
  • Proteasome Inhibitors / chemical synthesis
  • Proteasome Inhibitors / chemistry
  • Proteasome Inhibitors / pharmacology*
  • Rabbits
  • Structure-Activity Relationship

Substances

  • Hydrazines
  • Peptides
  • Proteasome Inhibitors
  • Chymotrypsin