Unlocking Cu(I)-Mediated Catalytic Pathways for Efficient ROS Generation by Incorporating an Oxazole-Based Histidine Surrogate into Cu(II)–ATCUN Complexes

Abstract

The catalytic redox activity of Cu(II) bound to the amino-terminal copper and nickel (ATCUN) binding motif (Xxx-Zzz-His, XZH) is stimulating the development of catalytic metallodrugs based on reactive oxygen species (ROS)-mediated biomolecule oxidation. However, low Cu(I) availability resulting from the strong Cu(II) binding affinity of the ATCUN motif is regarded as a limitation to efficient ROS generation. To address this, we replaced the imidazole moiety (pK a 7.0) of Gly−Gly− His−NH 2 (GGHa, a canonical ATCUN peptide) with thiazole (pK a 2.7) and oxazole (pK a 0.8), yielding GGThia and GGOxa, respectively. A newly synthesized amino acid, Fmoc-3-(4oxazolyl)-L-alanine, served as a histidine surrogate featuring an azole ring with the lowest pK a among known analogues. Despite similar square-planar Cu(II)−N 4 geometries being observed for the three Cu(II)−ATCUN complexes by electron paramagnetic resonance spectroscopy and X-ray crystallography, the azole modification enabled the Cu(II)−ATCUN complexes to exhibit significant rate enhancement for ROS-mediated DNA cleavage. Further analyses based on Cu(I)/Cu(II) binding affinities, electrochemical measurements, density functional theory calculations, and X-ray absorption spectroscopy indicated that the azole modification enhanced the accessibility of the Cu(I) oxidation state during ROS generation. Our oxazole/thiazole-containing ATCUN motifs provide a new design strategy for peptide ligands with modulated N donor ability, with potential applications in the development of ROS-mediated metallodrugs.

Trivalent Copper Ion-Mediated Dual Oxidation in the Copper-Catalyzed Fenton-Like System in the Presence of Histidine

“…The enhanced reactivity of both Cu­(II)-His 2 and Cu­(I)-His with H 2 O 2 likely results from the change in electronic properties of the central copper ion owing to the His-induced alteration in coordination geometry, including a higher shift in the reduction potential of the Cu­(II)/Cu­(I) couple. Several studies have reported more positive reduction potential values for the Cu­(II)/Cu­(I)-His containing compounds complexes ( E ° = 0.28–0.75 V − ) than those in the absence of ligands ( E ° = 0.153 V). In addition to His, a similar shift in the Cu­(II) reduction potential has been observed upon the introduction of other ligands (e.g., chloride ion), which consequently enhanced the degradation of organic contaminants. , In a similar manner, His can also elevate the reduction potential of the Cu­(III)/Cu­(II) couple, thereby enhancing the oxidation power of Cu­(III) against recalcitrant organic pollutants, which warrants further study.…”