Chromone-Based Antioxidant Copper(II) Complex with High Superoxide Dismutase Activity

Various low-molecular weight transition metal complexes mimic the function of superoxide dismutase enzymes (SODs) and can be applied as antioxidants in the medical treatment of diseases associated with elevated superoxide levels. In this aspect, chromone and its metal complexes are promising candidates as antioxidants; however, their low water solubility and limited metal-binding affinity prevent their applications. Now, we report the synthesis of a novel chromone-based ligand, ChroHis, that shows enhanced water solubility and complex formation reactions with copper(II). Solution equilibrium studies, supported by various types of spectroscopic methods, revealed that both chromone-3-carboxylic acid and ChroHis form stable copper(II) complexes. At physiological pH, chromone-3-carboxylic acid coordinates copper(II) via its keto and carboxylate groups to form a bis-complex, whereas ChroHis forms high stability dimeric complexes. Cyclic voltammetry confirmed that the complexes possess redox potentials within the optimal range for superoxide dismutation, and both stopped-flow kinetics and the McCord-Fridovich assay demonstrated excellent SOD activity. In vitro cell viability and long-term proliferation assays revealed that ChroHis and its copper(II) complex are nontoxic in a wide concentration range. The combined features of high SOD activity, thermodynamic stability, and low cytotoxicity suggest that the Cu(II)/ChroHis complex holds strong potential for future antioxidant applications.