Tricks with clicks: modification of peptidomimetic oligomers via copper-catalyzed azide-alkyne [3 + 2] cycloaddition

Abstract

This tutorial review examines recent developments involving use of Copper-catalyzed Azide-Alkyne [3 + 2] Cycloaddition (CuAAC) reactions in the synthesis, modification, and conformational control of peptidomimetic oligomers. CuAAC reactions have been used to address a variety of objectives including: (i) ligation of peptidomimetic oligomers; (ii) synthesis of ordered "foldamer" architectures; (iii) conjugation of ligands to peptidomimetic scaffolds; and (iv) macrocyclization of peptidomimetics using triazole linkages as conformational constraints. Variations in synthesis protocols, such as the use of different solvent systems, temperatures and copper species are evaluated herein to present a range of variables for the optimization of CuAAC reactions. The overall objectives of these studies are assessed to highlight the widespread applications of the products, which range from bioactive ligands to new materials.

Selectivity among Two Lectins: Probing the Effect of Topology, Multivalency and Flexibility of “Clicked” Multivalent Glycoclusters

“…We focused here on the synthesis of the tetravalent linear and cyclic oligomers and their conjugation to a carbohydrate probe through "click" chemistry. [45][46][47] The secondary amine of the linear tetrapropargylated b-peptoid 1 [44] was acetylated and the corresponding acetamide 2 was then conjugated to 1-azido-3,6-dioxaoct-8-yl-2,3,4,6-tetra-O-acetyl-b-d-galactopyranoside A [40,48] through CuAAC under microwave irradiation to afford the peracetylated glycoconjugate 3 (Scheme 1). Saponification of both the tert-butyl ester and acetates afforded the hydroxylated glycocluster 4.…”

The btp [2,6-bis(1,2,3-triazol-4-yl)pyridine] binding motif: a new versatile terdentate ligand for supramolecular and coordination chemistry

“…The CuAAC reaction has also been used to 'click' modifications onto the 4-pyridyl position of terdentate ligands, such as dpa derivatives in order to synthesise metal chelators, 76 form Ln(III) luminescent probes, 77 and graft these onto silica nanoparticles. 78 There are many review articles covering this area, such as the use of the CuAAC reaction in construction of dendrimers and polymeric architectures, 79 modification of peptidomimetic oligomers, 80 and construction of higher order interlocked supramolecular structures. 81 Schibli et al described the installation of triazolyl metal chelating sites into molecules in a single step using the CuAAC reaction as the 'click to chelate' approach.…”

Systematic replacement of amides by 1,4-disubstituted[1,2,3]triazoles in Leu-enkephalin and the impact on the delta opioid receptor activity

“…Both functions have hydrogen bond acceptor properties and a similar dipolar moment 7 . The triazole was rarely proved to be a weak hydrogen bond donor 8 .…”

“…In several peptidomimetics this extension induced no significant change to the biological activity 4,5 . Since the amide bonds in endogenous peptides are the primary site targeted by degrading enzymes, their replacement by triazole groups represents an efficient way to design analogs with enhanced biological half-life 7 .…”