ZFIN ID: ZDB-PUB-160330-8
Synthesis, Evaluation, and Metabolism of Novel [6]-Shogaol Derivatives as Potent Nrf2 Activators
Zhu, Y., Wang, P., Zhao, Y., Yang, C., Clark, A., Leung, T., Chen, X., Sang, S.
Date: 2016
Source: Free radical biology & medicine   95: 243-54 (Journal)
Registered Authors: Chen, Xiaoxin Luke, Leung, Tin Chung
Keywords: Metabolism, Nrf2 activators, Tg(gstp1:GFP) transgenic zebrafish model, [6]-Shogaol derivatives
MeSH Terms:
  • Animals
  • Animals, Genetically Modified/genetics
  • Antioxidants/administration & dosage
  • Antioxidants/chemical synthesis
  • Catechols/administration & dosage*
  • Catechols/chemical synthesis
  • Cysteine/metabolism
  • Glutathione S-Transferase pi/genetics
  • Heme Oxygenase-1/genetics
  • Humans
  • Kelch-Like ECH-Associated Protein 1/genetics*
  • NF-E2-Related Factor 2/genetics*
  • Oxidative Stress/drug effects*
  • Oxidative Stress/genetics
  • Signal Transduction/drug effects
  • Structure-Activity Relationship
  • Zebrafish/genetics
PubMed: 27021962 Full text @ Free Radic. Biol. Med.
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 (6S), using the Tg[glutathione S-transferase pi 1 (gstp1):green fluorescent protein (GFP)] transgenic zebrafish model. Investigation of structure-activity relationships of 6S 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 6S 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 6S 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 6S 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.