title: Synthetic chalcones with potent antioxidant ability on H₂O₂-induced apoptosis in PC12 cells.
abstract: Chalcone derivatives (E)-3-(4-hydroxy-3-methoxyphenyl)-1-(4-methoxyphenyl) prop-2-en-1-one and (E)-3-(4-hydroxyphenyl)-1-(4-methoxyphenyl) prop-2-en-1-one (Compounds 1 and 2) have been demonstrated to be potent anti-inflammatory agents in our previous study. In light of the relationship of intracellular mechanisms between anti-inflammatories and antioxidants, we further designed and synthesized a series of chalcone derivatives based on 1 and 2, to explore their antioxidant efficacy. The majority of the derivatives exhibited strong protective effects on PC12 (PC12 rat pheochromocytoma) cells exposed to H2O2, and all compounds were nontoxic. A preliminary structure-activity relationship was proposed. Compounds 1 and 1d ((E)-2-methoxy-4-(3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl) phenyl acrylate) exerted the action in a good dose-dependent manner. Quantitative RT-PCR (qRT-PCR) and western blot analysis showed that 1 and 1d significantly improve the expression of nuclear factor erythroid 2 p45-related factor 2 (Nrf2)-dependent antioxidant genes g-Glutamylcysteine Ligase Catalytic Subunit (GCLC) and heme oxygenase-1 (HO-1) and their corresponding proteins (γ-glutamyl cysteine synthase (γ-GCS) and HO-1) in PC12 cells. Inhibition of GCLC and HO-1 by specific inhibitors, L-buthionine-S-sulfoximine (BSO) and zinc protoporphyrin (ZnPP), respectively, partially reduce the protective effect of 1 and 1d. These data present a series of novel chalcone analogs, especially compounds 1 and 1d, as candidates for treating oxidative stress-related disease by activating the Nrf2-antioxidant responsive element (ARE) pathway.
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China. wjzwzmu@163.com.
authors.forename: Jian-Zhang
authors.initials: JZ
authors.lastname: Wu
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China. 15990761519@163.com.
authors.forename: Chan-Chan
authors.initials: CC
authors.lastname: Cheng
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China. shenlailai@126.com.
authors.forename: Lai-Lai
authors.initials: LL
authors.lastname: Shen
authors.affiliation: Institute of Sports Science, Wenzhou Medical University, Wenzhou 325035, China. wzk2001@163.com.
authors.forename: Zhan-Kun
authors.initials: ZK
authors.lastname: Wang
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China. wushoubiao@163.com.
authors.forename: Shou-Biao
authors.initials: SB
authors.lastname: Wu
authors.affiliation: College of Information Science and Computer Engineering, Wenzhou Medical University, Wenzhou 325035, China. liwulan@163.com.
authors.forename: Wu-Lan
authors.initials: WL
authors.lastname: Li
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China. honeybee13131@163.com.
authors.forename: Su-Hua
authors.initials: SH
authors.lastname: Chen
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China. zrpbarra@163.com.
authors.forename: Rong-Ping
authors.initials: RP
authors.lastname: Zhou
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China. qph@wzmc.edu.cn.
authors.forename: Pei-Hong
authors.initials: PH
authors.lastname: Qiu
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D047188:Chalcones / Q000737:chemistry / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats
chemical_list: D000975:Antioxidants; D047188:Chalcones; D006861:Hydrogen Peroxide