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

• 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
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm501027w

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.