In recent years, the epoxyketone moiety has emerged as a valuable pharmacophore, especially in the context of peptides. The variety of peptide epoxyketone natural products is vast, with many of these molecules displaying potent bioactivity. Epoxyketone-containing peptides have already demonstrated pharmaceutical relevance through the anti-cancer drug carfilzomib, which is derived from the natural product epoxomicin[1]. Alongside many other peptide epoxyketones, carfilzomib displays potent and specific inhibition of the proteasome[2]. Over the past several decades, the proteasome has been identified as a crucial medicinal target, with on-going exploration of proteasome inhibitors for the treatment of a range of conditions.
Despite their value as proteasome inhibitors, the synthesis of peptide epoxyketones remains challenging[3]. Significant effort is required to access the correct stereochemistry at the epoxyketone α-position, and challenges are often encountered with the chemical instability of the sensitive epoxyketone residue.
This poster will describe the development of a chemoenzymatic workflow to access peptide epoxyketones. Drawing upon our understanding of the biosynthetic pathway employed to produce peptide epoxyketones in vivo[4], a library of mutant enzymes has been prepared to catalyse the epoxyketone formation reaction. We have developed a photolabile protecting group strategy, which allows for the unmasking of the target substrate in tandem with the enzymatic reaction, enabling facile production of peptide epoxyketones. We will disclose our efforts to synthesise high-value epoxyketone targets using this methodology, such as the previously unsynthesised macyranone A and the chemotherapeutic agent carfilzomib. Development of an efficient synthesis of a variety of epoxyketone containing peptides will provide a pathway to their eventual widespread use in the clinic.