Synthesis and bioactivity evaluation of novel nuciferine derivatives with antihyperuricemia and nephroprotective effects
文献类型： 外文期刊
作者： Zhang, Yu-Kai 1 ; Chen, Jia-Shu 2 ; Wang, Min-Min 3 ; Wang, Chuan-Zeng 2 ; Wang, Mu-Xuan 2 ; Wang, Zhen 4 ; Yang, Qin-Liang 4 ; Sun, Bin 1 ; Sun, Jin-Yue 2 ; Liu, Yu-Fa 1 ; Liu, Chao 2 ;
作者机构： 1.Shandong Normal Univ, Shandong Prov Key Lab Clean Prod Fine Chem, Key Lab Mol & Nano Probes,Minist Educ, Coll Chem Chem Engn & Mat Sci,Collaborat Innovat, 88 East Wenhua Rd, Jinan 250014, Peoples R China
2.Shandong Acad Agr Sci, Inst Agrofood Sci & Technol, Key Lab Novel Food Resources Proc, Minist Agr & Rural Affairs,Key Lab Agroprod Proc, 202 Gongye North Rd, Jinan 250100, Peoples R China
3.Taian Tradit Chinese Med Hosp, Tai An 271000, Shandong, Peoples R China
4.Arura Tibetan Med Shandong Hlth Ind Co, Jinan 250100, Peoples R China
5.Shandong Acad Agr Sci, Modern Agr Res Inst Yellow River Delta, Dongying 257000, Peoples R China
关键词： Nuciferine derivatives; Synthesis; Hyperuricemia; URAT1 inhibitor; Nephroprotective
期刊名称：BIOORGANIC CHEMISTRY （ 影响因子：5.307； 五年影响因子：5.321 ）
ISSN： 0045-2068
年卷期： 2022 年 126 卷
页码：
收录情况： SCI
摘要： Hyperuricemia is a common metabolic disease with a series of complications. Nuciferine, a typical aporphine alkaloid natural compound extracted from the leaves of Nelumbo nucifera Gaertn., was confirmed to have an antihyperuricemia effect. In the present study, 30 novel nuciferine derivatives were designed and synthesized. The effects of all derivatives on the regulation of URAT1 were studied in a uric acid-induced HK 2 cell model with benzbromamne as a positive control. The results indicated that Compound 1j showed the optimal URAT1 inhibitory activity through repressing PI3K/Akt pathway in HK-2 cells and the inhibitory effect was similar to that of benzbromamne. In addition, in vivo experiments demonstrated that Compound 1j could reduce uric acid levels and ameliorate kidney damage in hyperuricemic mice. On the one hand, Compound 1j could inhibit the expression of URAT1 and GLUT9 to increase the uric acid excretion index. On the other hand, Compound 1j could regulate the TLR4/I kappa B alpha/NF-kappa B signaling pathway to reduce the levels of inflammatory cytokines, thereby alleviating kidney damage. Meanwhile, a molecular docking assay revealed the potential molecular binding power (-9.79 kcal/mol) between Compound 1j and URAT1, which was more tightly bound than the lead compound nuciferine (-7.44 kcal/mol). Based on these results, Compound 1j may be a future drug for the development of new potential antihyperuricemia and nephropmtective drug candidates.
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