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Discovery of a potent and highly ?1 specific proteasome inhibitor from a focused library of urea-containing peptide vinyl sulfones and peptide epoxyketones.

ABSTRACT: Syringolins, a class of natural products, potently and selectively inhibit the proteasome and show promising antitumour activity. To gain insight in the mode of action of syringolins, the ureido structural element present in syringolins is incorporated in oligopeptide vinyl sulfones and peptide epoxyketones yielding a focused library of potent new proteasome inhibitors. The distance of the ureido linkage with respect to the electrophilic trap strongly influences subunit selectivity within the proteasome. Compounds 13 and 15 are ?5 selective and their potency exceeds that of syringolin A. In contrast, 5 may well be the most potent ?1 selective compound active in living cells reported to date.

SUBMITTER: van der Linden WA

PROVIDER: S-EPMC3769973 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Discovery of a potent and highly β1 specific proteasome inhibitor from a focused library of urea-containing peptide vinyl sulfones and peptide epoxyketones.

van der Linden Wouter A WA Willems Lianne I LI Shabaneh Tamer B TB Li Nan N Ruben Mark M Florea Bogdan I BI van der Marel Gijs A GA Kaiser Markus M Kisselev Alexei F AF Overkleeft Herman S HS

Organic & biomolecular chemistry 20111122 1

Syringolins, a class of natural products, potently and selectively inhibit the proteasome and show promising antitumour activity. To gain insight in the mode of action of syringolins, the ureido structural element present in syringolins is incorporated in oligopeptide vinyl sulfones and peptide epoxyketones yielding a focused library of potent new proteasome inhibitors. The distance of the ureido linkage with respect to the electrophilic trap strongly influences subunit selectivity within the pr ...[more]

PMID: 22105930

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