Synthesis and biological evaluation of genipin derivatives as novel xanthine oxidase inhibitors for the anti-hyperuricemia and hepatorenal protection activity

Abstract

Hyperuricemia is a metabolic disorder caused by elevated uric acid (UA) level, which is closely related to the activity of xanthine oxidase (XOD) in the liver, inhibiting XOD activity has become one of major strategy in the treatment of hyperuricemia and its complications. In this study, a series of genipin derivatives were synthesized as novel XOD inhibitors. In which, the compound 4d, 5a, 5b, 5c and 5f exhibited the significant XOD inhibitory activity with the IC₅₀ values of 2.58 μM, 1.59 μM, 0.68 μM, 3.69 μM, and 2.03 μM, which was significantly lower than genipin (82.63 μM). Meanwhile, compound 4d, 5a, 5b, 5c and 5f showed non-cytotoxicity in normal HK-2 cells. Subsequently, compound 4d, 5a, 5b, 5c and 5f were evaluated in hyperuricemic model mice, and compound 5b showed the strongest anti-hyperuricemia and hepatorenal protection activity. Further research revealed that compound 5b could ameliorate pathological damage and fibrosis. Molecular mechanism indicated that compound 5b reduced UA accumulation in the kidney by regulating the expression of UA transport proteins and alleviated inflammatory response by regulating MAPK/NF-κB signaling pathway. In addition, compound 5b relieved oxidative stress and inflammatory response in the liver by inhibiting XOD activity. Kinetic analysis indicated that compound 5b was a mixed competitive inhibitor, and molecular docking confirmed the binding mode between compound 5b and XOD. Briefly, compound 5b was a potential XOD inhibitor for further application with anti-hyperuricemia and hepatorenal protection activity.

Keywords: Genipin derivatives; Hepatorenal protection; Hyperuricemia; Molecular mechanism; XOD inhibitor.