α‐Aminoxy Oligopeptides: Synthesis,Secondary Structure,and Cytotoxicity of a New Class of Anticancer Foldamers

α‐Aminoxy peptides are peptidomimetic foldamers with high proteolytic and conformational stability. To gain an improved synthetic access to α‐aminoxy oligopeptides we used a straightforward combination of solution‐ and solid‐phase‐supported methods and obtained oligomers that showed a remarkable anticancer activity against a panel of cancer cell lines. We solved the first X‐ray crystal structure of an α‐aminoxy peptide with multiple turns around the helical axis. The crystal structure revealed a right‐handed 2₈‐helical conformation with precisely two residues per turn and a helical pitch of 5.8 Å. By 2D ROESY experiments, molecular dynamics simulations, and CD spectroscopy we were able to identify the 2₈‐helix as the predominant conformation in organic solvents. In aqueous solution, the α‐aminoxy peptides exist in the 2₈‐helical conformation at acidic pH, but exhibit remarkable changes in the secondary structure with increasing pH. The most cytotoxic α‐aminoxy peptides have an increased propensity to take up a 2₈‐helical conformation in the presence of a model membrane. This indicates a correlation between the 2₈‐helical conformation and the membranolytic activity observed in mode of action studies, thereby providing novel insights in the folding properties and the biological activity of α‐aminoxy peptides.