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 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.
authors.affiliation: Laboratory of Bioorganic Chemistry Sloan Kettering Institute for Cancer Research 1275 York Avenue New York 10021, USA.
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Yang
authors.forename: Benjamin H B
authors.initials: BH
authors.lastname: Kwok
authors.forename: Songnian
authors.initials: S
authors.lastname: Lin
authors.forename: Michael A
authors.initials: MA
authors.lastname: Koldobskiy
authors.forename: Craig M
authors.initials: CM
authors.lastname: Crews
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Danishefsky
mesh_terms: 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
chemical_list: D009097:Multienzyme Complexes; D010456:Peptides, Cyclic; C408291:TMC-95A; C408292:TMC-95B; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex