title: α-Aminoxy Oligopeptides: Synthesis, Secondary Structure, and Cytotoxicity of a New Class of Anticancer Foldamers.
abstract: 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.
authors: Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf, 40225, Düsseldorf, Germany.
authors: Daniela
authors: D
authors: Diedrich
authors: Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf, 40225, Düsseldorf, Germany.
authors: Ana J Rodrigues
authors: AJ
authors: Moita
authors: Institut für Pharmazeutische Wissenschaften, Albert-Ludwigs-Universität Freiburg, 79104, Freiburg, Germany.
authors: Anja
authors: A
authors: Rüther
authors: Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf, 40225, Düsseldorf, Germany.
authors: Benedikt
authors: B
authors: Frieg
authors: Institut für Anorganische Chemie und Strukturchemie, Heinrich-Heine-Universität Düsseldorf, 40225, Düsseldorf, Germany.
authors: Guido J
authors: GJ
authors: Reiss
authors: X-Ray Facility and Crystal Farm, Heinrich-Heine-Universität Düsseldorf, 40225, Düsseldorf, Germany.
authors: Astrid
authors: A
authors: Hoeppner
authors: Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf, 40225, Düsseldorf, Germany.
authors: Thomas
authors: T
authors: Kurz
authors: Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf, 40225, Düsseldorf, Germany.
authors: Holger
authors: H
authors: Gohlke
authors: Institut für Pharmazeutische Wissenschaften, Albert-Ludwigs-Universität Freiburg, 79104, Freiburg, Germany.
authors: Steffen
authors: S
authors: Lüdeke
authors: Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf, 40225, Düsseldorf, Germany.
authors: Matthias U
authors: MU
authors: Kassack
authors: Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf, 40225, Düsseldorf, Germany.
authors: Finn K
authors: FK
authors: Hansen
mesh_terms: D008958:Models, Molecular; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry*; D017433:Protein Structure, Secondary; D012997:Solvents / Q000737:chemistry*
chemical_list: D009842:Oligopeptides; D012997:Solvents
keywords: antitumor agents; foldamers; helical structures; peptides; peptidomimetics