您好，欢迎访问山东省农业科学院文献资源数据库平台

Synthesis and biological evaluation of geniposide derivatives as inhibitors of hyperuricemia, inflammatory and fibrosis

文献类型： 外文期刊

作者： Chen, Jia-shu 1 ; Wang, Mu-xuan 2 ; Wang, Min-min 3 ; Zhang, Yu-kai 1 ; Guo, Xu 2 ; Chen, Ying-ying 2 ; Zhang, Meng-qi 2 ; Sun, Jin-yue 2 ; Liu, Yu-fa 1 ; Liu, Chao 2 ;

作者机构： 1.Shandong Normal Univ, Collaborat Innovat Ctr Functionalized Probes Chem, Shandong Prov Key Lab Clean Prod Fine Chem, Coll Chem Chem Engn & Mat Sci,Minist Educ,Key Lab, 88 East Wenhua Rd, Jinan 250014, Peoples R China

2.Shandong Acad Agr Sci, Minist Agr & Rural Affairs, Key Lab Agroprod Proc Technol Shandong Prov, Key Lab Novel Food Resources Proc,Inst Agrofood S, 202 Gongye North Rd, Jinan 250100, Peoples R China

3.Taian Tradit Chinese Med Hosp, Tai An 271000, Shandong, Peoples R China

关键词： Hyperuricemia; Geniposide derivatives; XOD inhibitor; Hyperuricemic nephritis and renal fibrosis; Molecular mechanism

期刊名称：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY （ 影响因子：7.088； 五年影响因子：6.427 ）

ISSN： 0223-5234

年卷期： 2022 年 237 卷

页码：

收录情况： SCI

摘要： Hyperuricemia is a metabolic disease caused by abnormal purine metabolism in the body. Long-term high levels of uric acid in the body will lead to gout and kidney disease. Xanthine oxidase (XOD) is a key enzyme in the pathogenesis of hyperuricemia. In this context, a series of geniposide derivatives were designed, synthesized and evaluated as xanthine oxidase inhibitors. Most of these compounds exhibited potent XOD inhibitory activities in vitro, and representatives 6a, 6c, 6g and 6j were found to be the most potent inhibitors against the enzyme with IC50 values of 2.15 +/- 1.03, 1.37 +/- 0.26, 4.14 +/- 0.79 and 1.86 +/- 0.13 mu M, which were 33.03-158.37 fold more active than geniposide, respectively. Compounds 6a, 6c, 6g and 6j were evaluated in hyperuricemia mice, and the results demonstrated that compound 6c showed the strongest anti-hyperuricemia and renal protective activity in vivo. Subsequently, the molecular mechanism of compound 6c was studied in this investigation. In vitro cell experiments showed that compound 6c inhibited the inflammation of HK-2 cells under high uric acid conditions by inhibiting the expressions of TGF-beta, TNF-alpha and IL-1 beta, and reduced the cell fibrosis by decreasing the expressions of alpha-SMA and Collagen I. The results of the mice experiments indicated that compound 6c efficiently decreased the level of serum uric acid (SUA) in hyperuricemia mice by inhibiting the XOD activity. Moreover, compound 6c effectively reduced the urate accumulation in the kidney and simultaneously decreased inflammation by regulating the expression of the TLR4/I kappa B alpha/NF-kappa B signaling pathway. In addition, consistent with cell experiments, compound 6c also reduced renal fibrosis in hyperuricemia mice, which may be due to compound 6c inhibiting the expression of inflammatory factor TGF-beta. Furthermore, a molecular docking study was performed to gain insight into the binding mode of compound 6c with XOD. These results suggest that compound 6c has the potential to be developed into a novel medicine to reduce blood uric acid and treat renal diseases caused by hyperuricemia.

  • 相关文献
作者其他论文 更多>>
置顶
购物车
反馈

© 京ICP备09089781号-29 主办单位：山东省农业科学院文献资源数据库平台

学术资源： 中国农业科学院 农业专业知识服务系统 农科联盟资源共建共享平台 中国农业科技文献与信息服务平台 中国农业期刊集成服务平台