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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

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Published copy (DOI)

Author(s)

  • Wouter A. Van Der Linden
  • Lianne I. Willems
  • Tamer B. Shabaneh
  • Nan Li
  • Mark Ruben
  • Bogdan I. Florea
  • Gijs A. Van Der Marel
  • Markus Kaiser
  • Alexei F. Kisselev
  • Herman S. Overkleeft

Department/unit(s)

Publication details

JournalOrganic and Biomolecular Chemistry
DatePublished - 7 Jan 2012
Issue number1
Volume10
Number of pages14
Pages (from-to)181-194
Original languageEnglish

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 β5 selective and their potency exceeds that of syringolin A. In contrast, 5 may well be the most potent β1 selective compound active in living cells reported to date.

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