title: Peptido sulfonyl fluorides as new powerful proteasome inhibitors.
abstract: A new class of potent proteasome inhibitors is described, of which the members contain an amino acid inspired sulfonyl fluoride as the electrophilic trap. In total, 24 peptido sulfonyl fluoride inhibitors have been designed and synthesized, which were inspired by the backbone sequences of the proteasome inhibitors bortezomib, epoxomicin, and Cbz-Leu(3)-aldehyde. Nine of them were very potent proteasome inhibitors, the best of which had an IC(50) of 7 nM. A number of the peptido sulfonyl fluoride inhibitors were found to be highly selective for the β5 proteasome subunit.
authors.affiliation: Department of Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, P.O. Box 80082, 3508 TB Utrecht, The Netherlands.
authors.forename: Arwin J
authors.initials: AJ
authors.lastname: Brouwer
authors.forename: Anika
authors.initials: A
authors.lastname: Jonker
authors.forename: Paul
authors.initials: P
authors.lastname: Werkhoven
authors.forename: Ethan
authors.initials: E
authors.lastname: Kuo
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.forename: Nerea
authors.initials: N
authors.lastname: Gallastegui
authors.forename: Johan
authors.initials: J
authors.lastname: Kemmink
authors.forename: Bogdan I
authors.initials: BI
authors.lastname: Florea
authors.forename: Michael
authors.initials: M
authors.lastname: Groll
authors.forename: Herman S
authors.initials: HS
authors.lastname: Overkleeft
authors.forename: Rob M J
authors.initials: RM
authors.lastname: Liskamp
mesh_terms: D057809:HEK293 Cells; D006801:Humans; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D010455:Peptides; D061988:Proteasome Inhibitors; D021122:Protein Subunits; D013450:Sulfones; D046988:Proteasome Endopeptidase Complex