Synthesis, Structure, and Cytotoxicity of Urukthapelstatin A Polyazole Cyclopeptide Analogs

Abstract

Analogs of the natural product urukthapelstatin A that belongs to the rare family of polyazole cyclopeptides were synthesized and their cytotoxic activities were determined to gather data toward structure–activity relationships. Crucial steps within the convergent syntheses were a macrothiolactonization and a subsequent aza‐Wittig reaction to install the heterocyclic backbone. The synthesis design was proven to be generally suitable for the formation of these azole containing cyclopeptides. Two analogs were structurally characterized by X‐ray crystallography which unveiled the planar assembly of the five catenated azoles as well as a unique hydrogen bond network. A conformational comparison to the known natural products was conducted. Cytotoxicity data showed the importance of key structural features with respect to the bioactivity including the phenyl ring attached to the eastern oxazole and the rigid, lipophilic tripeptide section.