An overview of NRF2-activating compounds bearing α,β-unsaturated moiety and their antioxidant effects

The surge of scientific interest in the discovery of Nuclear Factor Erythroid 2 (NFE2)-Related Factor 2 (NRF2)-activating molecules underscores the importance of NRF2 as a therapeutic target especially for oxidative stress. The chemical reactivity and biological activities of several bioactive compounds have been linked to the presence of α,β-unsaturated structural systems. The α,β-unsaturated carbonyl, sulfonyl and sulfinyl functional groups are reportedly the major α,β-unsaturated moieties involved in the activation of the NRF2 signaling pathway. The carbonyl, sulfonyl and sulfinyl groups are generally electron-withdrawing groups, and the presence of the α,β-unsaturated structure qualifies them as suitable electrophiles for Michael addition reaction with nucleophilic thiols of cysteine residues within the proximal negative regulator of NRF2, Kelch-like ECH-associated protein 1 (KEAP1). The physicochemical property such as good lipophilicity of these moieties is also an advantage because it ensures solubility and membrane permeability required for the activation of the cytosolic NRF2/KEAP1 system. This review provides an overview of the reaction mechanism of α,β-unsaturated moiety-bearing compounds with the NRF2/KEAP1 complex, their pharmacological properties, structural activity-relationship and their effect on antioxidant and anti-inflammatory responses. As the first of its kind, this review article offers collective and comprehensive information on NRF2-activators containing α,β-unsaturated moiety with the aim of broadening their therapeutic prospects in a wide range of oxidative stress-related diseases.