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 ?. 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.
Diedrich, Daniela,Moita, Ana J. Rodrigues,Rüther, Anja,Frieg, Benedikt,Reiss, Guido J.,Hoeppner, Astrid,Kurz, Thomas,Gohlke, Holger,Lüdeke, Steffen,Kassack, Matthias U.,Hansen, Finn K.
p. 17600 - 17611
(2016/11/28)
Structure-activity relationships of novel endomorphin-2 analogues with N-O turns induced by α-aminoxy acids
Endomorphin-2 (H-Tyr-Pro-Phe-Phe-NH2, EM-2) is a putative endogenous μ-opioid receptor ligand. To study the structure-activity relationship against its receptor, we introduced N-O turns into EM-2 and got the analogues with potent affinities for μ-opioid receptor. Our results indicated that N-O turn structures at the Pro2-aminoxy-Phe 3 position of EM-2 analogues played important roles for their affinities. These novel analogues with N-O turns provided a new approach to develop potent analgesics related to EM-2.
A cyclic hexapeptide comprising alternating α-aminoxy and α-amino acids is a selective chloride ion receptor
In nonpolar solvents, the cyclic hexapeptide 2, which comprises alternating D-α-amino and D-α-aminoxy acids, adopts a C3-symmetric conformation with alternating eight (N-O turns)- and seven (γ turns)-membered-ring hydrogen bonds. A series of anion-binding studies has suggested that 2 can function as an effective anion receptor that not only displays a high selectivity for chloride ions, but also the capability to extract chloride ions from aqueous solutions into organic phases.
Yang, Dan,Li, Xiang,Sha, Yao,Wu, Yun-Dong
p. 3005 - 3009
(2007/10/03)
Synthesis of optically active phthaloyl D-aminooxy acids from L-amino acids or L-hydroxy acids as building blocks for the preparation of aminooxy peptides
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Shin,Lee,Lee,Jung,Lee,Yoon
p. 7667 - 7675
(2007/10/03)
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