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

Chiara Testa, Mario Scrima, Manuela Grimaldi, Anna M. D'Ursi, Marvin L. Dirain, Nadège Lubin-Germain, Anamika Singh, Carrie Haskell-Luevano, Michael Chorev, Paolo Rovero, Anna M. Papini

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)9424-9434
Number of pages11
JournalJournal of medicinal chemistry
Volume57
Issue number22
DOIs
StatePublished - Nov 26 2014

Bibliographical note

Publisher Copyright:
© 2014 American Chemical Society.

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