In:
Chemistry – A European Journal, Wiley, Vol. 22, No. 49 ( 2016-12-05), p. 17600-17611
Kurzfassung:
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 2 8 ‐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 2 8 ‐helix as the predominant conformation in organic solvents. In aqueous solution, the α‐aminoxy peptides exist in the 2 8 ‐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 2 8 ‐helical conformation in the presence of a model membrane. This indicates a correlation between the 2 8 ‐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.
Materialart:
Online-Ressource
ISSN:
0947-6539
,
1521-3765
DOI:
10.1002/chem.201602521
Sprache:
Englisch
Verlag:
Wiley
Publikationsdatum:
2016
ZDB Id:
1478547-X