文献类型：期刊文献

英文题名：Engineering piperlongumine-inspired analogs as Nrf2-dependent neuroprotectors against oxidative damage by an electrophilicity-based strategy

作者：Wang, Qi[1];Lin, Dong[1];Liu, Xue-Feng[1,2];Dai, Fang[1];Jin, Xiao-Jie[2];Zhou, Bo[1]

第一作者：Wang, Qi

通信作者：Dai, F[1];Zhou, B[1];Jin, XJ[2]

机构：[1]Lanzhou Univ, State Key Lab Appl Organ Chem, Lanzhou 730000, Gansu, Peoples R China;[2]Gansu Univ Chinese Med, Coll Pharm, Gansu Univ Key Lab Mol Med & Chinese Med Prevent &, 35 Dingxi East Rd, Lanzhou 730000, Gansu, Peoples R China

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

通信机构：[1]corresponding author), Lanzhou Univ, State Key Lab Appl Organ Chem, Lanzhou 730000, Gansu, Peoples R China;[2]corresponding author), Gansu Univ Chinese Med, Coll Pharm, Gansu Univ Key Lab Mol Med & Chinese Med Prevent &, 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：2023

卷号：194

起止页码：298

外文期刊名：FREE RADICAL BIOLOGY AND MEDICINE

收录：;Scopus(收录号：2-s2.0-85144077489);WOS:【SCI-EXPANDED(收录号:WOS:000913732000001)】；

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：Piperlongumine; Electrophilicity; Nrf2; Neuroprotection; Oxidative stress

摘要：Oxidative stress contributes significantly to the development of neurodegenerative diseases, thus developing nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent neuroprotectors is highly required for either pre-vention or treatment of these diseases. This work highlights an electrophilicity-based strategy that allows finding more active Nrf2-dependent neuroprotectors than natural piperlongumine (PL). Electrophilic modification was applied on both the exocylic and endocyclic Michael acceptors of PL, which includes placement of an electron-withdrawing trifluoromethyl group on its aromatic ring in the ortho, meta, or para position to the exocyclic olefin, and further introduction of an electron-withdrawing alpha-chlorine on its lactam ring. From a panel of PL analogs, we identified PLCl-4CF3, characterized by the presence ofp-trifluoromethyl group and alpha-chlorine, to be significantly superior to the parent PL in protecting PC12 cells from oxidative damage induced by 6-hydroxydopamine hy-drochloride. Mechanistic studies reveal that the increased electrophilicity of PLCl-4CF3 in its two Michael ac-ceptors allows its ability to covalently modify Cys-151 at Keap1, facilitating inhibition against Nrf2 ubiquitination, translocation of Nrf2 into the nucleus, induction of phase 2 enzymes and final protection of PC12 cells from oxidative damage.