文献类型：期刊文献

英文题名：Developing dietary curcumin mono-carbonyl piperidinone analogs as Nrf2-dependent cytoprotectors against oxidative damage: Structure-activity relationship and mechanisms

作者：Liu, Xue-Feng[1,2,3];Wang, Qi[1];Zheng, Jia-Fang[1];Chai, Zuo-Hu[1];Dai, Fang[1];Jin, Xiao-Jie[3];Zhou, Bo[1]

第一作者：Liu, Xue-Feng;刘雪枫

通信作者：Dai, F[1];Zhou, B[1];Jin, XJ[2]

机构：[1]Lanzhou Univ, State Key Lab Appl Organ Chem, 222 Tianshui St S, Lanzhou 730000, Gansu, Peoples R China;[2]Lanzhou Univ, Sch Pharm, 222 Tianshui St S, Lanzhou 730000, Gansu, Peoples R China;[3]Gansu Univ Tradit Chinese Med, Coll Pharm, 35 Dingxi East Rd, Lanzhou 730000, Gansu, Peoples R China

第一机构：Lanzhou Univ, State Key Lab Appl Organ Chem, 222 Tianshui St S, Lanzhou 730000, Gansu, Peoples R China

通信机构：[1]corresponding author), Lanzhou Univ, State Key Lab Appl Organ Chem, 222 Tianshui St S, Lanzhou 730000, Gansu, Peoples R China;[2]corresponding author), Gansu Univ Tradit Chinese Med, Coll Pharm, 35 Dingxi East Rd, Lanzhou 730000, Gansu, Peoples R China.|[1073501e14fb35863569f]甘肃中医药大学药学院（西北中藏药协同创新中心办公室）;[10735]甘肃中医药大学;

年份：2022

卷号：186

起止页码：66

外文期刊名：FREE RADICAL BIOLOGY AND MEDICINE

收录：;Scopus(收录号：2-s2.0-85129948938);WOS:【SCI-EXPANDED(收录号:WOS:001125208900004)】；

基金：This work was supported by the National Natural Science Foundation of China (Grant Nos. 22177045 and 31100607).

语种：英文

外文关键词：Curcumin; Nrf2; Michael acceptor; Cytoprotection; Oxidative stress

摘要：Developing nuclear factor erythroid-2 related factor 2 (Nrf2)-dependent cytoprotectors against oxidative damage is of concern because they can effectively reduce the risk of oxidative stress-related diseases, such as cancer and inflammation. This work was aimed to develop more active Nrf2-dependent cytoprotectors than curcumin, a well-known dietary Nrf2 activator and cancer chemopreventive agent. Herein we designed a panel of curcumin-inspired mono-carbonyl piperidinone analogs differentiated by placing distinct electron-withdrawing and electron-donating groups on its two aromatic rings in the ortho, meta, or para position to the linker of alpha, beta-unsaturated piperidinone. Among these, the ortho-fluorine-substituted CN-2F surfaced as a promising lead molecule, which was significantly superior to the parent curcumin in protecting HepG2 cells from oxidative damage induced by tert-butyl hydroperoxide. Mechanically, by virtue of its Michael receptor units and ortho-substituted mode, CN-2F activated Nrf2 signaling by covalently modifying Cys-151 and Cys-288 residues at Keap1, promoting phosphorylation of JNK, ERK and p38, as well as inhibiting Nrf2 degradation. This work reveals the structural determinants and the activity mechanisms of CN-2F as an Nrf2-dependent cytoprotector, and gives useful information on how to design curcumin-inspired Nrf2 activators and cytoprotectors.