姜黄素
化学
氧化应激
氧化磷酸化
共价键
激活剂(遗传学)
残留物(化学)
生物化学
立体化学
药理学
受体
有机化学
医学
作者
Xuefeng Liu,Qi Wang,Jia-Fang Zheng,Zuo-Hu Chai,Fang Dai,Xiaojie Jin,Bo Zhou
标识
DOI:10.1016/j.freeradbiomed.2022.05.009
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 α, β-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.
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