CuI-Catalyzed Azide–Alkyne Intramolecular i-to-(i+4) Side-Chain-to-Side-Chain Cyclization Promotes the Formation of Helix-Like Secondary Structures

A solid-phase assembly of model peptides derived from human parathyroid hormone-related protein (11–19) containing ω-azido- and ω-yl-α-amino acid residues in positions i and i+4 was cyclised in solution by an intramolecular CuI-catalyzed azide–alkyne 1,3-dipolar Huisgen cycloaddition. These series of heterodetic cyclo-nonapeptides varied in the size of the disubstituted 1,2,3-triazolyl-containing bridge, the location and the orientation of the 1,2,3-triazolyl moiety within the bridge. The 1,2,3-triazolyl moiety, presented at either 1,4- or 4,1-orientation, is flanked by side chains containing 1–4 CH2 groups that result in bridges comprised from 4–7 CH2 groups connecting residues 13 and 17. Comprehensive conformational analysis employing CD, NMR and molecular dynamics reveals the conformational propensities of these heterodetic cyclo-nonapeptides. Cyclo-nonapeptides containing either the 7 methylene bridge (VII and VIII) or the 4 methylene bridge (II) are unstructured in structure-promoting solvent. Cyclo-nonapeptide I in which the 1,4-disubstituted 1,2,3-triazolyl is flanked by 3 and 1 CH2 groups in proximity to the respective residues 13 and 17, is stabilized in a noncanonical structure. All the other heterodetic cyclo-nonapeptides (III–VI) in which the 1,2,3-triazolyl is flanked by a total of 5 or 6 CH2 groups nicely accommodate α-helical structures and reproduce very closely the helical structure stabilized by the analogous cyclo-nonapeptide in which Lys13 and Asp17 are bridged by the isosteric lactam. These studies suggest that the bioorthogonal i-to-(i+4) side-chain-to-side-chain cyclization via the prototypic “click reaction” offers a new and powerful approach for generating stable helix mimetic structures.