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J Med Chem. 2014 Nov 26;57(22):9424-34. doi: 10.1021/jm501027w. Epub 2014 Nov 13.

1,4-disubstituted-[1,2,3]triazolyl-containing analogues of MT-II: design, synthesis, conformational analysis, and biological activity.

Author information

1
Laboratoire SOSCO & PeptLab@UCP, EA4505, University of Cergy-Pontoise , 5 mail Gay-Lussac, Neuville sur Oise, F-95031 Cergy-Pontoise Cedex, France.

Abstract

Side chain-to-side chain cyclizations represent a strategy to select a family of bioactive conformations by reducing the entropy and enhancing the stabilization of functional ligand-induced receptor conformations. This structural manipulation contributes to increased target specificity, enhanced biological potency, improved pharmacokinetic properties, increased functional potency, and lowered metabolic susceptibility. The Cu(I)-catalyzed azide-alkyne 1,3-dipolar Huisgen's cycloaddition, the prototypic click reaction, presents a promising opportunity to develop a new paradigm for an orthogonal bioorganic and intramolecular side chain-to-side chain cyclization. In fact, the proteolytic stable 1,4- or 4,1-disubstituted [1,2,3]triazolyl moiety is isosteric with the peptide bond and can function as a surrogate of the classical side chain-to-side chain lactam forming bridge. Herein we report the design, synthesis, conformational analysis, and functional biological activity of a series of i-to-i+5 1,4- and 4,1-disubstituted [1,2,3]triazole-bridged cyclopeptides derived from MT-II, the homodetic Asp(5) to Lys(10) side chain-to-side chain bridged heptapeptide, an extensively studied agonist of melanocortin receptors.

PMID:
25347033
PMCID:
PMC4255721
DOI:
10.1021/jm501027w
[Indexed for MEDLINE]
Free PMC Article

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