Simplified Synthetic TMC-95A/B Analogues Retain the Potency of Proteasome Inhibitory Activity

• Published in: Chembiochem : a European journal of chemical biology Vol. 4; no. 6; pp. 508 - 513
• Main Authors: Yang, Zhi-Qiang, Kwok, Benjamin H.B, Lin, Songnian, Koldobskiy, Michael A, Crews, Craig M, Danishefsky, Samuel J
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley-VCH Verlag 06.06.2003; WILEY-VCH Verlag; WILEY‐VCH Verlag
• Subjects: Animals; Catalysis; Cattle; Cysteine Endopeptidases - metabolism; Drug Design; inhibitors; Molecular Structure; Multienzyme Complexes - antagonists & inhibitors; Multienzyme Complexes - metabolism; peptides; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - chemistry; Peptides, Cyclic - pharmacology; proteasome; Proteasome Endopeptidase Complex; Structure-Activity Relationship; structure-activity relationships; synthesis
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.200300560

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.