Cui catalyzed azide-alkyne intramolecular i-to-(i+4) side-chain-to-SideChain cyclization promotes the formation of Helix-Like secondary structures

Abstract

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 1,4or 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 a-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 struc-tures © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.