Evaluation of dicopper azacryptand complexes in aqueous CuAAC reactions and their tolerance toward biological thiols

Abstract

A series of dicopper azacryptand complexes was evaluated in copper-catalysed azide–alkyne cycloaddition (CuAAC) in water at 37 °C. It was found that they showed high activity at concentrations as low as 5 μM. These dinuclear catalysts were more susceptible toward inhibition by cysteine rather than glutathione under the conditions tested. Interestingly, the mononuclear copper complexes that are ligated by tripodal amine ligands, also exhibited good catalytic activity in aqueous media and showed similar sensitivity toward biological thiols as that of the dinuclear complexes. Our results suggest that the azacryptand catalysts are too structurally flexible to adequately prevent interactions of their metal centres with external nucleophiles. However, further steric tuning of the ligand structure might enable more effective substrate gating in future studies.