- α-Aminoxy Oligopeptides: Synthesis, Secondary Structure, and Cytotoxicity of a New Class of Anticancer Foldamers
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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.
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p. 17600 - 17611
(2016/11/28)
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- Efficient preparation of aminoxyacyl amides, aminoxy hybrid peptides, and α-aminoxy peptides
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(Chemical Equation Presented) N-(Pg-α-aminoxy acids) 1a-g are converted to N-(Pg-α-aminoxyacyl)benzotriazoles 2a-g, which react under mild conditions with amines, α-amino acids/α-dipeptides, and α-aminoxy acids to give aminoxyacyl amides 3a-g, (3e+3e′), and (3g+3g′), aminoxy hybrid peptides 4a-h, (4a+4a′), 6a-d, 9a-e, (9a+9a′), and (9b+9b′), and α-aminoxy peptides 10a,b in good yields without racemization. 2009 American Chemical Society.
- Katritzky, Alan R.,Avan, Ilker,Tala, Srinivasa R.
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supporting information; experimental part
p. 8690 - 8694
(2010/01/16)
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- Structure-activity relationships of novel endomorphin-2 analogues with N-O turns induced by α-aminoxy acids
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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.
- Wei, Jie,Shao, Xuan,Gong, Maozhen,Zhu, Beibei,Cui, Yuxin,Gao, Yanfeng,Wang, Rui
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p. 2986 - 2989
(2007/10/03)
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