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.

Chemical Composition and In Vitro Antioxidant Activity of Sida rhombifolia L. Volatile Organic Compounds

“…It was well established that α-β-unsaturated moiety-bearing compounds could activate the NRF2/KEAP1 signaling pathway, which can be described as the chief regulator of endogenous antioxidant responses to oxidative stress. Moreover, the reactivity of α-β-unsaturated moiety-bearing compounds explained the VOCs’ significant free radical scavenging activity [ 31 ]. Thus, the traditional uses of S. rhombifolia to treat various ailments may be due to the main components mentioned above.…”

Phenothiazines: Nrf2 activation and antioxidant effects

“…Therefore, the activation of Nrf2 signaling pathway may represent a possible therapeutic strategy for several diseases in which oxidative stress and inflammation are implicated. [42,43] EGBUJOR ET AL.…”

Medicinal Chemistry Insights into the Development of Small-Molecule Kelch-Like ECH-Associated Protein 1-Nuclear Factor Erythroid 2-Related Factor 2 (Keap1–Nrf2) Protein–Protein Interaction Inhibitors

“…Under stress conditions, Keap1 functions as the sensor for various reactive substances from endogenous and exogenous environments. , These inducers can covalently modify the sensitive cysteine residues of Keap1 and impair the precise assembly of the Cul3–Keap1–Nrf2 complex, finally leading to the activation of Nrf2. , Particularly, three representative models have been proposed to describe the molecular mechanism of Nrf2 activation in the induced state, including the Cul3-dissociation model, the hinge and latch model, and the conformation cycling model (Figure ). ,, According to the Cul3-dissociation model, the stimulating substances can covalently react with the cysteine residues in the BTB domain of Keap1 to disturb the interaction between Cul3 and Keap1, thus encumbering Nrf2 ubiquitination. , Some classical electrophilic Nrf2 activators have been confirmed to activate Nrf2 by inducing the dissociation of Cul3 from Keap1. − In the hinge and latch model, the ETGE motif with high binding affinity works as a hinge to make Nrf2 tightly bind to the Keap1 homodimer, while the DLG motif with low binding affinity exists as a latch to regulate the status of ubiquitination. Only when both of these motifs bind to the Keap1 homodimer will the ubiquitination of Nrf2 occur. , Under stress conditions, the stimulating signals can covalently react with the cysteine residues located at the IVR domain of Keap1, thereby inducing the dissociation of the DLG motif from Keap1 and hindering the ubiquitination of Nrf2 .…”