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 beta1 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.
Baldisserotto
Anna
A
Department of Pharmaceutical Sciences and Biotechnology Center, University of Ferrara, Ferrara, Italy.
Marastoni
Mauro
M
Lazzari
Ilaria
I
Trapella
Claudio
C
Gavioli
Riccardo
R
Tomatis
Roberto
R
D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004795:Enzyme Stability; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D010649:Phenylalanine / Q000737:chemistry*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors
D015853:Cysteine Proteinase Inhibitors; D061988:Proteasome Inhibitors; D010649:Phenylalanine; D046988:Proteasome Endopeptidase Complex