The syrbactins are a class of natural products that have been discovered to effectively induce apoptosis in various cancer cell lines through irreversible binding and inhibition of the proteasome. The eukaryotic proteasome is a large multifunctional protein complex consisting of three proteolytically active subunits involved in the degradation of proteins. Inhibition of these sites causes an accumulation of proteins within the cell, ultimately causing apoptosis. There has been great interest in the creation of syrbactin analogs to explore structure-activity relationships and improve the potency of these compounds for use as potential cancer treatments. However, compound solubility is a persistent issue and further research is needed to improve drug uptake as well as overall efficacy of syrbactin-based proteasome inhibition. Previous structure-activity relationships of syrbactin analogs inspired our synthesis of a unique set of syrbactin derivatives in efforts to create next-generation proteasome inhibitors with increased solubility and inhibitory properties. This work relies on synthetic methods for their key macrolactam substructure developed in earlier total syntheses of syrbactin natural products. A novel set of syrbactin derivatives has been proposed and synthesized, and their biological activities have been evaluated.

Synthesis and evaluation of novel proteasome-inhibiting syrbactin derivatives

251st National Meeting (2016)

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