1. Design, synthesis and bioactive evaluation of geniposide derivatives for antihyperuricemic and nephroprotective effects.
- Author
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Wang, Muxuan, Chen, Jiashu, Zhang, Ruirui, Guo, Xinyan, Chen, Daxia, Guo, Xu, Chen, Yingying, Wu, Yuhao, Sun, Jinyue, Liu, Yufa, and Liu, Chao
- Subjects
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CELLULAR signal transduction , *MOLECULAR docking , *XANTHINE oxidase , *ENZYME kinetics , *URIC acid , *CELL survival , *TRIAZINE derivatives - Abstract
[Display omitted] • A series of novel geniposide derivatives were designed and synthesized for discovering efficient XOD inhibitor. • Compound 2e displayed the most XOD inhibitory effect in vitro and in vivo. • Compound 2e can also repair kidney damage by inhibiting the expression of TNF-α and IL-1β signaling pathways. • Kinetics analysis revealed that compound 2e is a reversible mixed competitive inhibitor. • Molecular docking study indicated iridoid and glycosyl moiety of compound 2e were critical for binding to the XOD active site. 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 IC 50 value of 6.67 ± 0.46 µM. 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-κB 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. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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