Inhibition of the 20S proteasome confers one method of cancer therapy. This research explores the synthesis of macrocyclic bimodal inhibitors modeled after the natural product TMC-95A, which inhibits the proteasome by way of a hydrogen-bonding network. Our inhibitors additionally contain a functional group that reacts with the catalytic nucleophile of the enzyme. The synthetic strategy consists of preparation of a tripeptide by solid phase synthesis followed by N-terminal coupling of a non-natural phenylalanine analog.

Synthesis of bimodal inhibitors of the 20S proteasome

243rd National Meeting (2012)

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