Inhibition of xanthine oxidase by copper-gallate coordination polymers and its mechanistic study

Hyperuricemia (HUA) is a metabolic disease caused by elevated uric acid levels, with xanthine oxidase (XOD) as the key enzyme in uric acid production. Current treatments primarily use XOD inhibitors (e.g., allopurinol and febuxostat), but their lack of antioxidant activity limits their ability to counteract oxidative stress in HUA. Gallic acid (GA), a polyphenol with antioxidant properties, weakly inhibits XOD but is insufficient alone. Transition metal ions like Cu²⁺ are potent reversible XOD inhibitors, yet excessive concentrations cause toxicity. The coordination reaction effectively reduces metal ion toxicity while partially preserving the inherent antioxidant properties of polyphenols. Using gallic acid (GA) as a ligand with Cu²⁺, we synthesized Cu-GA complex, which forms a stable coordination polymer that minimally releases free Cu²⁺ in water. Cu-GA demonstrated superior XOD inhibition compared to allopurinol (AP), GA, and Cu²⁺ alone, functioning as a reversible inhibitor to reduce uric acid levels. Additionally, it maintained significant antioxidant activity while showing substantially lower cytotoxicity in LO2 and AML12 cells than free Cu²⁺. In conclusion, for Cu-GA, the coordination reaction retained the inhibitory effect of Cu 2+ on XOD, while conferring some antioxidant effects, and also reduced the biotoxicity of Cu 2+ .