Macrocyclization of the ATCUN Motif Controls Metal Binding and Catalysis

We report the design, synthesis, and characterization of macrocyclic analogues of the amino-terminal copper and nickel binding (ATCUN) motif. These macrocycles have altered pH transitions for metal binding, and unlike linear ATCUN motifs, the optimal cyclic peptide 1 binds Cu(II) selectively over Ni(II) at physiological pH. UV–vis and EPR spectroscopy showed that cyclic peptide 1 can coordinate Cu(II) or Ni(II) in a square planar geometry. Metal binding titration and ESI-MS data revealed a 1:1 binding stoichiometry. Macrocyclization allows for coordination of Cu(II) or Ni(II) as in linear ATCUN motifs, but with enhanced DNA cleavage by the Cu(II)-1 complex relative to linear analogues. The Cu(II)-1 complex was also capable of producing diffusible hydroxyl radicals, which is unique among ATCUN motifs and most other common copper(II) chelators.