- 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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- An unusual conformation of α-haloamides due to cooperative binding with zincated porphyrins
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CD and NMR spectroscopic evidence of cooperative binding between an α-halogen atom and a carboxamide group with a zinc porphyrin leads to an unprecedented conformation for the determination of the absolute stereochemistry of α-haloamides (α-halocarboxylic acids derivatized with 1,4-phenylenediamine) through the use of exciton-coupled circular dichroism (ECCD). With the use of chiral lactams, whose rotomeric contributions are minimized, both ECCD and NMR spectroscopy demonstrate that the porphyrin favors binding to the side of the sterically more demanding halogen atom as compared to the smaller hydrogen atom. In all, the data is strongly suggestive of an unusual conformation not observed before for α-chiral amides. A mnemonic for determining the absolute stereochemistry of α-halogenated carboxylic acids is provided.
- Tanasova, Marina,Yang, Qifei,Olmsted, Courtney C.,Vasileiou, Chrysoula,Li, Xiaoyong,Anyika, Mercy,Borhan, Babak
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supporting information; experimental part
p. 4242 - 4253
(2011/02/25)
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- Asymmetric Reduction of Chiral Acetophenone Oxime Ethers to Optically Active Primary Amines
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Chiral oxime ethers were synthesized from Na salt of acetophenone oxime and chiral halides, tosylates, or N-tosylaziridines which were derived from β-pinene or α-amino acids.Asymmetric reduction of the chiral oxime ether with LiAlH4 or BH3*THF gave the optically active primary amine.
- Itsuno, Shinichi,Tanaka, Kazuo,Ito, Koichi
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p. 1133 - 1136
(2007/10/02)
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