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 biological potency, improved pharmacokinetic properties, increased functional potency, and lowered metabolic susceptibility. The Cu-catalyzed azide−alkyne 1,3dipolar Huisgen’s cycloaddition, the prototypic click reaction, presents a promising opportunity to develop a new paradigm for an orthogonal bioorganic and intramolecular side chain-toside chain cyclization. In fact, the proteolytic stable 1,4or 4,1disubstituted [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 1,4and 4,1disubstituted [1,2,3]triazole-bridged cyclopeptides derived from MT-II, the homodetic Asp to Lys side chain-to-side chain bridged heptapeptide, an extensively studied agonist of melanocortin receptors.