| Summary: | Due to their robust antioxidant properties, phenolic acids and their analogs are extensively studied for their ability to activate cellular antioxidant pathways, including nuclear factor (erythroid-derived-2)-like 2 (Nrf2)-antioxidant response element (ARE) pathway. Caffeic, ferulic, and gallic acid are well-studied members of phenolic acids. Constant efforts are made to improve the pharmacological effects and bioavailability of phenolic acids by synthesizing their chemical derivatives. This study determines how modifications of the chemical structure of these phenolic acids affect their antioxidant and cytoprotective activities. We have selected six superior antioxidant compounds (<b>12</b>, <b>16</b>, <b>26</b>, <b>35</b>, <b>42</b>, and <b>44</b>) of the 48 caffeic acid phenethyl ester (CAPE) analogs based on their ability to scavenge free radicals in vitro using standard antioxidant assays. These compounds exhibited minimal toxicity as indicated by cell cycle and cytochrome C release assays. Among these compounds, <b>44</b>, the ketone analog of CAPE, exhibited the ability to increase p-Nrf2 (Ser40) levels in 293T cells (<i>p</i> < 0.05). Further, <b>44</b>, exhibited its antioxidant effect in <i>Drosophila Melanogaster</i> as indicated by an increase in mRNA levels of Nrf2 and GPx (<i>p</i> < 0.05). Finally, the ability of <b>44</b> to activate the antioxidant pathway was abolished in the presence of extracellular signal-regulated kinase (ERK) inhibitor in 293T cells. Thus, we identify <b>44</b>, the ketone analog of CAPE, as a unique antioxidant molecule with the function of ERK-mediated Nrf2 activation.
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