| Summary: | Substituted <i>N</i>-phenyl cinnamamide derivatives were designed and synthesized to confirm activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway by the electronic effect on beta-position of Michael acceptor according to introducing the R<sup>1</sup> and R<sup>2</sup> group. Compounds were screened using the Nrf2/antioxidant response element (ARE)-driven luciferase reporter assay. Compound <b>1g</b> showed desirable luciferase activity in HepG2 cells without cell toxicity. mRNA and protein expression of Nrf2/ARE target genes such as NAD(P)H quinone oxidoreductase 1, hemeoxygenase-1, and glutamate-cysteine ligase catalytic subunit (GCLC) were upregulated by compound <b>1g</b> in a concentration-dependent manner. Treatment with <b>1g</b> resulted in increased endogenous antioxidant glutathione, showing strong correlation with enhanced GCLC expression for synthesis of glutathione. In addition, <i>tert</i>-butyl hydroperoxide (<i>t</i>-BHP)-generated reactive oxygen species were significantly removed by <b>1g</b>, and the results of a cell survival assay in a <i>t</i>-BHP-induced oxidative cell injury model showed a cytoprotective effect of <b>1g</b> in a concentration dependent manner. In conclusion, the novel compound <b>1g</b> can be utilized as an Nrf2/ARE activator in antioxidative therapy.
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