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

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• 作者：Chiara Testa ; Mario Scrima ; Manuela Grimaldi ; Anna M. D鈥橴rsi ; Marvin L. Dirain ; Nad猫ge Lubin-Germain ; Anamika Singh ; Carrie Haskell-Luevano ; Michael Chorev ; Paolo Rovero ; Anna M. Papini
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：November 26, 2014
• 年：2014
• 卷：57
• 期：22
• 页码：9424-9434
• 全文大小：546K
• ISSN：1520-4804

文摘

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鈥揳lkyne 1,3-dipolar Huisgen鈥檚 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.