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

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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.