Imine Resveratrol Analogues: Molecular Design, Nrf2 Activation and SAR Analysis

<div><p>Resveratrol is a natural phenol with protective effects against cancer and inflammation-related diseases. Its mechanism of action involves the activation of nuclear factor E2 p45-related factor 2 (Nrf2), which plays a key role in regulation of genes driven by antioxidant response element (ARE). Inspired by the effect of resveratrol, here we synthesized a series of imine resveratrol analogs (IRAs), evaluated their abilities to activate Nrf2 by using cell based ARE-reporter assay. After the first-round screening, preliminary and quantitative structure-activity relationship (SAR) was analyzed, and the structural features determining Nrf2 activation ability were proposed. Two novel IRAs were designed and subsequently synthesized, namely 2-methoxyl-3,6-dihydroxyl-IRA and 2,3,6-trihydroxyl-IRA. They were proved to be the most potent Nrf2 activators among the IRAs.</p></div

Structures (A) and ARE-luciferase activities (B) of 33, 34 and resveratrol.

<p>ARE reporter cells were exposed to <b>33</b>, <b>34</b> and resveratrol (7.5 µM, 15 µM and 30 µM) for 24 h. The value for cells treated with vehicle DMSO (0.1% v/v) was set at 1. Results are from three separate experiments. Values shown are mean ± SD.</p

SAR results from initial screening of IRAs.

<p>SAR results from initial screening of IRAs.</p

Synthesized IRAs and their effects on ARE-luciferase activity.

<p>ARE reporter cells were exposed to 7.5 µM, 15 µM or 30 µM IRA for 24 h. The value for cells treated with vehicle DMSO (0.1% v/v) was set at 1. Results are from three separate experiments.</p>a<p>Due to cytotoxicity of <b>9</b>.</p

ARE-luciferase activities in response to 6-OH IRAs.

<p>ARE reporter cells were exposed to (15 µM) for 24 h. The value for cells treated with vehicle DMSO (0.1% v/v) was set at 1. Results are from three separate experiments.</p

Proposed model for the adduct formation, fixation of IRA, and its reaction with Keap1.

<p>Proposed model for the adduct formation, fixation of IRA, and its reaction with Keap1.</p