Mixing of peptides and electrophilic traps gives rise to potent, broad-spectrum proteasome inhibitors.
The synthesis and evaluation of hybrid proteasome inhibitors that contain structural elements of the known inhibitors bortezomib, epoxomicin and peptide vinyl sulfones is described. From the panel of 15 inhibitors some structure activity relationships can be deduced with regard to inhibitory activity in relation to peptide recognition element, inhibitor size and nature of the electrophilic trap. Further, the panel contains one of the most potent peptide-based pan-proteasome inhibitors reported to date.
Verdoes
Martijn
M
Bio-organic synthesis, Leiden Institute of Chemistry, Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands.
Florea
Bogdan I
BI
van der Linden
Wouter A
WA
Renou
Didier
D
van den Nieuwendijk
Adrianus M C H
AM
van der Marel
Gijs A
GA
Overkleeft
Herman S
HS
D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D055672:Static Electricity; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D010455:Peptides; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex