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Chembiochem. 2003 Jun 6;4(6):508-13.

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

Author information

1
Laboratory of Bioorganic Chemistry Sloan Kettering Institute for Cancer Research 1275 York Avenue New York 10021, USA.

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 C8 position of TMC-95s can be replaced with a simple allylamide. The asymmetric center at C36 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.

PMID:
12794861
PMCID:
PMC2556569
DOI:
10.1002/cbic.200300560
[Indexed for MEDLINE]
Free PMC Article

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