Cu-I-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 omega-azido- and omega-yl-alpha-amino acid residues in positions i and i+4 was cyclised in solution by an intramolecular Cu-I-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 cvclo-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 non-canonical 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 alpha-helical structures and reproduce very closely the helical structure stabilized by the analogous cyclo-nonapeptide in which Lys(13) and Asp(17) 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.