title: Design, synthesis, and evaluation of curcumin derivatives as Nrf2 activators and cytoprotectors against oxidative death.
abstract: Activation of nuclear factor erythroid-2-related factor 2 (Nrf2) has been proven to be an effective means to prevent the development of cancer, and natural curcumin stands out as a potent Nrf2 activator and cancer chemopreventive agent. In this study, we synthesized a series of curcumin analogs by introducing the geminal dimethyl substituents on the active methylene group to find more potent Nrf2 activators and cytoprotectors against oxidative death. The geminally dimethylated and catechol-type curcumin analog (compound 3) was identified as a promising lead molecule in terms of its increased stability and cytoprotective activity against the tert-butyl hydroperoxide (t-BHP)-induced death of HepG2 cells. Mechanism studies indicate that its cytoprotective effects are mediated by activating the Nrf2 signaling pathway in the Michael acceptor- and catechol-dependent manners. Additionally, we verified by using copper and iron ion chelators that the two metal ion-mediated oxidations of compound 3 to its corresponding electrophilic o-quinone, contribute significantly to its Nrf2-dependent cytoprotection. This work provides an example of successfully designing natural curcumin-directed Nrf2 activators by a stability-increasing and proelectrophilic strategy.
authors.affiliation: State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China.
authors.forename: Zhi-Shan
authors.initials: ZS
authors.lastname: Tu
authors.affiliation: State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China.
authors.forename: Dan-Dan
authors.initials: DD
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China. Electronic address: daifang@lzu.edu.cn.
authors.forename: Fang
authors.initials: F
authors.lastname: Dai
authors.affiliation: State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China. Electronic address: bozhou@lzu.edu.cn.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhou
mesh_terms: D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002396:Catechols / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D003474:Curcumin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D019610:Cytoprotection / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000819:agonists* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000975:Antioxidants; D002396:Catechols; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D003474:Curcumin; C034221:catechol
keywords: Catechol; Curcumin; Cytoprotective activity; Michael acceptor; Nrf2