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

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

  • Bioorg Chem. 2025 Dec:167:109279. doi: 10.1016/j.bioorg.2025.109279.
Hui Sun 1,  Jia-Shu Chen 2,  Bo Zhang 3,  Cheng-Ju Xu 4,  Wei-Jian Wang 5,  Nan Chen 1,  Nilufar Z Mamadalieva 6,  Mu-Xuan Wang 7,  Ning-Yang Li 8
Affiliations

Affiliations

  • 1 College of Food Science and Engineering, Ocean University of China, Qingdao 266003, PR China.
  • 2 Key Laboratory of Novel Food Resources Processing, Ministry of Agriculture and Rural Affairs/Institute of Food & Nutrition Science and Technology, Shandong Academy of Agricultural Sciences, Jinan 250100, PR China. Electronic address: [email protected].
  • 3 Institute of Plant Protection, Shandong Academy of Agricultural Sciences, Jinan, PR China.
  • 4 Shandong Fengxiangyuan Food Co., Ltd, Binzhou, PR China.
  • 5 Qingdao Hengxing University of Science and Technology, Qingdao 266100, PR China.
  • 6 Institute of the Chemistry of Plant Substances of the Academy Sciences of Uzbekistan, Tashkent 100170, Uzbekistan.
  • 7 Key Laboratory of Novel Food Resources Processing, Ministry of Agriculture and Rural Affairs/Institute of Food & Nutrition Science and Technology, Shandong Academy of Agricultural Sciences, Jinan 250100, PR China. Electronic address: [email protected].
  • 8 College of Food Science and Engineering, Ocean University of China, Qingdao 266003, PR China. Electronic address: [email protected].
PMID: 41289908 DOI: 10.1016/j.bioorg.2025.109279
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.

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