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Review
. 2020 Apr 22:2020:1675957.
doi: 10.1155/2020/1675957. eCollection 2020.

Coumarins as Modulators of the Keap1/Nrf2/ARE Signaling Pathway

Emad H M Hassanein  1 , Ahmed M Sayed  2 , Omnia E Hussein  3 , Ayman M Mahmoud  3
Affiliations
Review

Coumarins as Modulators of the Keap1/Nrf2/ARE Signaling Pathway

Emad H M Hassanein et al. Oxid Med Cell Longev. .

Abstract

The Keap1/Nrf2/ARE system is a central defensive mechanism against oxidative stress which plays a key role in the pathogenesis and progression of many diseases. Nrf2 is a redox-sensitive transcription factor controlling a variety of downstream antioxidant and cytodefensive genes. Nrf2 has a powerful anti-inflammatory activity mediated via modulating NF-κB. Therefore, pharmacological activation of Nrf2 is a promising therapeutic strategy for the treatment/prevention of several diseases that are underlined by both oxidative stress and inflammation. Coumarins are natural products with promising pharmacological activities, including antioxidant, anticancer, antimicrobial, and anti-inflammatory efficacies. Coumarins are found in many plants, fungi, and bacteria and have been widely used as complementary and alternative medicines. Some coumarins have shown an ability to activate Nrf2 signaling in different cells and animal models. The present review compiles the research findings of seventeen coumarin derivatives of plant origin (imperatorin, visnagin, urolithin B, urolithin A, scopoletin, esculin, esculetin, umbelliferone, fraxetin, fraxin, daphnetin, anomalin, wedelolactone, glycycoumarin, osthole, hydrangenol, and isoimperatorin) as antioxidant and anti-inflammatory agents, emphasizing the role of Nrf2 activation in their pharmacological activities. Additionally, molecular docking simulations were utilized to investigate the potential binding mode of these coumarins with Keap1 as a strategy to disrupt Keap1/Nrf2 protein-protein interaction and activate Nrf2 signaling.

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Conflict of interest statement

The authors report no conflict of interests.

Figures

Figure 1
Figure 1
Chemical structure of selected coumarin-derived compounds.
Figure 2
Figure 2
Nrf2 activity is augmented by exogenous and/or endogenous stressors. Under basal conditions, Keap1 mediates Nrf2 ubiquitination and subsequent proteasomal degradation through acting as an adaptor molecule for CUL-E3 ligase. Upon exposure to exogenous and/or endogenous stressors, such as xenobiotics and ROS, respectively, Nrf2 translocates into the nucleus and binds to the ARE to activate cytoprotective molecules, including antioxidant and detoxification enzymes. Superoxide dismutase (SOD) mediates the dismutation of superoxide radicals (O2-·) leading to the formation of hydrogen peroxide (H2O2). Catalase and glutathione peroxidase (GPx) catalyze the degradation of H2O2. HO-1 catalyzes degradation of heme to biliverdin and bilirubin which are potential antioxidants [49]. CO: carbon monoxide.
Figure 3
Figure 3
Surface map of Keap1 protein (a) and chemical structure of (S,R,S) (b). The colored residues represent the active site of Keap1 which is involved directly in the interaction with the inhibitor (S,R,S) (PDB ID: 4l7b) and include Y334, S363, R380, N414, R415, S508, S555, Y572, and S602.
Figure 4
Figure 4
The binding pocket of Keap1 includes Y334, S363, R380, N414, R415, S508, S555, Y572, and S602. These residues were used for the site-specific docking of coumarin derivatives into Keap1.
Figure 5
Figure 5
Docking models of imperatorin, urolithin B, urolithin A, and esculin with Keap1. All the compounds are rich with polar groups and form hydrogen bonds with the polar, negatively, and positively charged amino acids in the vicinity of the active site of Keap1.
Figure 6
Figure 6
Docking models of fraxin, wedelolactone, glycycoumarin, and hydrangenol with Keap1. All the compounds are rich with polar groups and form hydrogen bonds with the polar, negatively and positively charged amino acids in the vicinity of the active site of Keap1.
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