Design, synthesis and bioactive evaluation of geniposide derivatives for antihyperuricemic and nephroprotective effects

文献类型： 外文期刊

第一作者： Wang, Muxuan

作者： Wang, Muxuan;Zhang, Ruirui;Guo, Xu;Chen, Yingying;Sun, Jinyue;Liu, Chao;Chen, Jiashu;Liu, Yufa;Guo, Xinyan;Chen, Daxia;Wu, Yuhao

作者机构：

关键词： Hyperuricemia; Geniposide derivatives; XOD inhibitor; Nephroprotective effect; Molecular mechanism

期刊名称：BIOORGANIC CHEMISTRY （ 影响因子：5.275； 五年影响因子：5.252 ）

ISSN： 0045-2068

年卷期： 2021 年 116 卷

页码：

收录情况： SCI

摘要： Hyperuricemia is a principal factor mediating gout and kidney damage, and xanthine oxidase (XOD) is a key enzyme in the pathogenesis of hyperuricemia. In this context, a series of geniposide derivatives were designed and synthesized, and antihyperuricemic and nephroprotective effects of all derivatives was evaluated in vitro and in vivo. Compound 2e emerged as the most potent XOD inhibitor, with an IC50 value of 6.67 +/- 0.46 mu M. Simultaneously, cell viability, ROS generation, and SOD levels assay showed that compound 2e could repair the damage of HKC cells by inhibiting the oxidative stress response. The results of the study indicated compound 2e significantly decreased uric acid levels by inhibiting the XOD activity, and repaired kidney damage by inhibiting the expression of TLR4/TLR2/MyD88/NF-kappa B and NALP3/ASC/caspase-1 signaling pathways. Enzyme inhibition kinetics suggested that compound 2e functioned via reversible mixed competitive inhibition. Moreover, a molecular docking study was performed to gain insight into the binding mode of compound 2e with XOD. These results suggest that geniposide derivatives were potential to be developed into a novel medicine to reveal healthy benefits in natural prevention and reduction risk of hyperuricemia and kidney damage.

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