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.
The title compound, C18H12N2O2, was synthesized from a dinitrobiphenylbenzene derivative using a novel modification of the Cadogan reaction. The reaction has several possible ring-closed products and the title compound was separated as the major product. The X-ray crystallographic study revealed that the carbazole compound crystallizes in the monoclinic P\overline{1} space group and possesses a single closed Cadogan ring. There are two independent molecules in the asymmetric unit. In the crystal, the molecules are linked by N—H...O hydrogen bonding.
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