Simplified synthetic TMC-95A/B analogues retain the potency of proteasome inhibitory activity.
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.
Yang
Zhi-Qiang
ZQ
Laboratory of Bioorganic Chemistry Sloan Kettering Institute for Cancer Research 1275 York Avenue New York 10021, USA.
Kwok
Benjamin H B
BH
Lin
Songnian
S
Koldobskiy
Michael A
MA
Crews
Craig M
CM
Danishefsky
Samuel J
SJ
D000818:Animals; D002384:Catalysis; D002417:Cattle; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015195:Drug Design; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D013329:Structure-Activity Relationship
D009097:Multienzyme Complexes; D010456:Peptides, Cyclic; C408291:TMC-95A; C408292:TMC-95B; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex