1,4-Disubstituted-[1,2,3]triazolyl-Containing Analogues of MT-II: Design, Synthesis, Conformational Analysis, and Biological Activity

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 bio...

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Published in:Journal of medicinal chemistry 2014-11, Vol.57 (22), p.9424-9434
Main Authors: Testa, Chiara, Scrima, Mario, Grimaldi, Manuela, D’Ursi, Anna M, Dirain, Marvin L, Lubin-Germain, Nadège, Singh, Anamika, Haskell-Luevano, Carrie, Chorev, Michael, Rovero, Paolo, Papini, Anna M
Format: Article
Language:English
Subjects:
Azides - chemistry
Chemistry, Pharmaceutical - methods
Copper - chemistry
Drug Design
HEK293 Cells
Humans
Lactams - chemistry
Ligands
Linear Models
Magnetic Resonance Spectroscopy - methods
Metallothionein - chemistry
Molecular Conformation
Peptides - chemistry
Receptors, Melanocortin - agonists
Structure-Activity Relationship
Triazoles - chemistry
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Summary: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 CuI-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 Asp5 to Lys10 side chain-to-side chain bridged heptapeptide, an extensively studied agonist of melanocortin receptors.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm501027w