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

   


Authors: Yang, Z. Q.; Kwok, B. H. B.; Lin, S.; Koldobskiy, M. A.; Crews, C. M.; Danishefsky, S. J.
Article Title: Simplified synthetic TMC-95A/B analogues retain the potency of proteasome inhibitory activity
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.
Keywords: unclassified drug; drug activity; protein function; animals; proteasome; proteasome inhibitor; proteasome endopeptidase complex; inflammation; drug potency; drug structure; drug design; drug synthesis; structure activity relation; structure-activity relationship; peptides; cattle; molecular structure; catalysis; structure analysis; multienzyme complexes; synthesis; peptides, cyclic; structure-activity relationships; cyclopeptide; amide; inhibitors; cysteine endopeptidases; cancer; priority journal; article; tmc 95a; tma 95b
Journal Title: ChemBioChem
Volume: 4
Issue: 6
ISSN: 1439-4227
Publisher: Wiley V C H Verlag Gmbh  
Date Published: 2003-06-06
Start Page: 508
End Page: 513
Language: English
DOI: 10.1002/cbic.200300560
PUBMED: 12794861
PROVIDER: scopus
PMCID: PMC2556569
DOI/URL:

http://www.scopus.com/inward/record.url?eid=2-s2.0-0038575020&partnerID=40&md5=72c1e978f6b7eb872083cfdfaf602dd2
Notes: Export Date: 12 September 2014 -- Source: Scopus
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MSK Authors
  1. Zhi-Qiang Yang
    5 Yang
  2. Songnian Lin
    6 Lin
  3. Samuel J Danishefsky
    539 Danishefsky
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