Journal Article

Synthesis, Evaluation, and Metabolism of Novel [6]-Shogaol Derivatives as Potent Nrf2 Activators

April 01, 2016

Synthesis, Evaluation, and Metabolism of Novel [6]-Shogaol Derivatives as Potent Nrf2 Activators. Free Radical Biology and Medicine, March 25, 2016. Yindong Zhu (a), Pei Wang (a), Yantao Zhao (a), Chun Yang (a,b), Anderson Clark (c), TinChung Leung (c), Xiaoxin Chen (d), Shengmin Sang (a).

Author Affiliations

a Laboratory for Functional Foods and Human Health, Center for Excellence in Post-Harvest Technologies, North Carolina Agricultural and Technical State University, North Carolina Research Campus, 500 Laureate Way, Kannapolis, NC 28081, USA
b Department of Colorectal Surgery, General Hospital of Ningxia Medical University, Yinchuan 750004, P.R. China
c Nutrition Research Program, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, North Carolina Research Campus, 500 Laureate Way, Kannapolis, NC 28081, USA
d Cancer Research Program, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Center University, 700 George Street, Durham, NC 27707, USA

Abstract

Oxidative stress is a central component of many chronic diseases. The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2 p45-related factor 2 (Nrf2) system is a major regulatory pathway of cytoprotective genes against oxidative and electrophilic stress. Activation of the Nrf2 pathway plays crucial roles in the chemopreventive effects of various inducers. In this study, we developed a novel class of potent Nrf2 activators derived from ginger compound, [6]-shogaol (6 S), using the Tg[glutathione S-transferase pi 1 (gstp1):green fluorescent protein (GFP)] transgenic zebrafish model. Investigation of structure-activity relationships of 6 S derivatives indicates that the combination of an α,β-unsaturated carbonyl entity and a catechol moiety in one compound enhances the Tg(gstp1:GFP) fluorescence signal in zebrafish embryos. Chemical reaction and in vivo metabolism studies of the four most potent 6 S derivatives showed that both α,β-unsaturated carbonyl entity and catechol moiety act as major active groups for conjugation with the sulfhydryl groups of the cysteine residues. In addition, we further demonstrated that 6 S derivatives increased the expression of Nrf2 downstream target, heme oxygenase-1, in both a dose- and time-dependent manner. These results suggest that α,β-unsaturated carbonyl entity and catechol moiety of 6 S derivatives may react with the cysteine residues of Keap1, disrupting the Keap1-Nrf2 complex, thereby liberating and activating Nrf2. Our findings of natural product-derived Nrf2 activators lead to design options of potent Nrf2 activators for further optimization.

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