Extraordinary metabolic stability of peptides containing α-aminoxy acids.
ABSTRACT The metabolic stability of peptides containing a mixed sequence of α-aminoxy acids and α-amino acids is significantly improved compared to peptides composed of only natural α-amino acids. The introduction of an α-aminoxy acid into peptide chain dramatically improves the stability of the amide bonds immediately before and after it. These peptides containing α-aminoxy acids represent excellent structural scaffold for the design of metabolically stable and biologically active peptides.
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ABSTRACT: We have synthesized a series of gamma-aminoxy acids, including unsubstituted and gamma4-Ph-, gamma4-alkyl-, and gamma(3,4)-cyclohexyl-substituted systems. Coupling of these monomers to oligomers can be realized using EDCI/HOBt (or HOAt) as the coupling agent. gamma-Aminoxy peptides can form 10-membered-ring intramolecular hydrogen bonds-so-called "gamma N-O turns"-between adjacent residues, the extent of which is controlled by the nature of the side chain of each gamma-aminoxy acid residue, increasing from the unsubstituted gamma-aminoxy peptide to the gamma4-alkyl aminoxy peptides to the gamma4-phenyl- and gamma(3,4)-cyclohexyl-substituted aminoxy peptides. The presence of two consecutive homochiral 10-membered-ring intramolecular hydrogen bonds leads to the formation of a novel helical structure. Theoretical studies on a series of model peptides rationalize very well the experimentally observed conformational features of these gamma-aminoxy peptides.Journal of the American Chemical Society 02/2008; 130(2):743-55. · 10.68 Impact Factor
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ABSTRACT: We have investigated, using NMR, IR, and CD spectroscopy and X-ray crystallography, the conformational properties of peptides 1-10 of beta(3)-aminoxy acids (NH(2)OCHRCH(2)COOH) having different side chains on the beta carbon atom (e.g., R = Me, Et, COOBn, CH(2)CH(2)CH=CH(2), i-Bu, i-Pr). The beta N-O turns and beta N-O helices that involve a nine-membered-ring intramolecular hydrogen bond between NH(i)(+2) and CO(i), which have been found previously in peptides of beta(2,2)-aminoxy acids (NH(2)OCH(2)CMe(2)COOH), are also present in those beta(3)-aminoxy peptides. X-ray crystal structures and NMR spectral analysis reveal that, in the beta N-O turns and beta N-O helices induced by beta(3)-aminoxy acids, the N-O bond could be either anti or gauche to the C(alpha)-C(beta) bond depending on the size of the side chain; in contrast, only the anti conformation was found in beta(2,2)-aminoxy peptides. Both diamide 1 and triamide 9 exist in different conformations in solution and in the solid state: parallel sheet structures in the solid state and predominantly beta N-O turn and beta N-O helix conformations in nonpolar solvents. Theoretical studies on a series of model diamides rationalize very well the experimentally observed conformational features of these beta(3)-aminoxy peptides.Journal of the American Chemical Society 07/2004; 126(22):6956-66. · 10.68 Impact Factor
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ABSTRACT: The conformational properties of peptides 1-3 of gamma-aminoxy acids have been investigated by using FT-IR, NMR spectroscopy, and X-ray crystallography. Diamide 1 consisting of unsubstituted gamma-aminoxy acid cannot form intramolecular hydrogen bond. A novel gamma N-O turn involving a 10-membered-ring intramolecular hydrogen bond between NHi+2 and COi is formed in gamma4-aminoxy peptides 2 and 3. Triamides 3 prefers a new helical structure featuring two consecutive gamma N-O turns. Therefore, gamma4-aminoxy peptides represent new peptidomimetic foldamers.Journal of the American Chemical Society 01/2005; 126(49):15980-1. · 10.68 Impact Factor