An Overview of NRF2-Activating Compounds Bearing α,β-Unsaturated Moiety and Their Antioxidant Effects

Abstract

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.

Keywords: KEAP1; NRF2; Parkinson’s disease; anti-inflammatory; antioxidant; carbonyl; sulfinyl; sulfonyl; α,β-unsaturated moiety.

Scheme 1

A resonance description of the transmission of electrophilic character to the beta-carbon of α,β-unsaturated carbonyl system (1).

Scheme 2

A schematic view of the electrophilic beta-carbon (indicated with asterisks) of α,β-unsaturated carbonyl (1), sulfonyl (2), sulfinyl (3) and some NRF2-activating compounds containing these α,β-unsaturated moieties (4–7). The asterisks represents the point at which thiols of cysteines are most likely to attack.

Scheme 3

Reaction mechanisms of α,β-unsaturated (A) carbonyl, (B) sulfonyl and (C) sulfinyl moieties. The nucleophilic attack of the thiol of the KEAP1 cysteine residues on the β carbon of the carbonyl group is followed by 1,4-addition reaction in which the thiol bonds to carbon in position 1 and hydrogen bonds to oxygen in position 4. It undergoes tautomerization to form adducts which facilitates the nuclear translocation of NRF2 (A). The reaction of α,β-unsaturated sulfonyl (B) and α,β-Unsaturated sulfinyl (C) with thiols of the KEAP1 cysteine residue also enable NRF2 translocation.

Scheme 4

Mechanism of activation of KEAP1-NRF2-ARE pathway by α,β-unsaturated moieties. In pro-oxidant condition, the exposure to electrophilic α,β-unsaturated moieties alters the structure of NRF2/KEAP1 complex, thus inhibiting NRF2 ubiquitination and creating a non-functional KEAP1 complex. As NRF2 is not released by KEAP1, it saturates all binding sites of KEAP1, allowing newly translated NRF2 to bypass KEAP1 and translocate to the nucleus.

Scheme 5

Structure–activity relationship of α,β-unsaturated moiety-bearing compounds.