C-terminal constrained phenylalanine as a pharmacophoric unit in peptide-based proteasome inhibitors

Here we report the synthesis and biological properties of peptide-based molecules bearing constrained analogues of phenylalanine at the C-terminal. Compounds were tested as proteasome subunits' inhibitors. Dehydro-peptides showed good inhibition, in particular against trypsin-like (T-L) proteasome activity while some C-terminal Tic-derivatives inhibit only caspase-like activity in enzymatic β1 subunits with a certain degree of efficacy. The best analogues of the series demonstrated good resistance to proteolysis and a capacity to permeate the cell membrane.

Graphical abstractNew peptide-based proteasome inhibitors bearing constrained Phe at C-terminal were synthesized and tested.Figure optionsDownload full-size imageDownload as PowerPoint slide