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Int. J. Mol. Sci. 2014, 15(10), 18525-18539;

Synthetic Chalcones with Potent Antioxidant Ability on H2O2-Induced Apoptosis in PC12 Cells

Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
Institute of Sports Science, Wenzhou Medical University, Wenzhou 325035, China
College of Information Science and Computer Engineering, Wenzhou Medical University, Wenzhou 325035, China
These authors contributed equally to this work.
Authors to whom correspondence should be addressed.
Received: 27 August 2014 / Revised: 24 September 2014 / Accepted: 28 September 2014 / Published: 14 October 2014
(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells 2014)
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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. View Full-Text
Keywords: chalcone derivatives; antioxidant; PC12 cells; Nrf2-ARE pathway; GCLC; HO-1 chalcone derivatives; antioxidant; PC12 cells; Nrf2-ARE pathway; GCLC; HO-1

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Wu, J.-Z.; Cheng, C.-C.; Shen, L.-L.; Wang, Z.-K.; Wu, S.-B.; Li, W.-L.; Chen, S.-H.; Zhou, R.-P.; Qiu, P.-H. Synthetic Chalcones with Potent Antioxidant Ability on H2O2-Induced Apoptosis in PC12 Cells. Int. J. Mol. Sci. 2014, 15, 18525-18539.

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