Simplified synthetic TMC-95A/B analogues retain the potency of proteasome inhibitory activity

Zhi Qiang Yang, Benjamin H.B. Kwok, Songnian Lin, Michael A. Koldobskiy, Craig M. Crews, Samuel J. Danishefsky

Research output: Contribution to journalArticlepeer-review

Abstract

The proteasome regulates diverse intracellular processes, including cell-cycle progression, antigen presentation, and inflammatory response. Selective inhibitors of the proteasome have great therapeutic potential for the treatment of cancer and inflammatory disorders. Natural cyclic peptides TMC-95A and B represent a new class of noncovalent, selective proteasome inhibitors. To explore the structure-activity relationship of this class of proteasome inhibitors, a series of TMC-95A/B analogues were prepared and analyzed. We found that the unique enamide functionality at the C-8 position of TMC-95s can be replaced with a simple allylamide. The asymmetric center at C-36 that distinguishes TMC-95A from TMC-95B but which necessitates a complicated separation of the two compounds can be eliminated. Therefore, these findings could lead to the development of more accessible simple analogues as potential therapeutic agents.

Original languageEnglish (US)
Pages (from-to)508-513
Number of pages6
JournalChemBioChem
Volume4
Issue number6
DOIs
StatePublished - Jun 6 2003
Externally publishedYes

Keywords

  • Inhibitors
  • Peptides
  • Proteasome
  • Structure-activity relationships
  • Synthesis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

Fingerprint

Dive into the research topics of 'Simplified synthetic TMC-95A/B analogues retain the potency of proteasome inhibitory activity'. Together they form a unique fingerprint.

Cite this