Activation of Nrf2 signaling pathway by natural and synthetic chalcones: a therapeutic road map for oxidative stress

ABSTRACT

Introduction:

Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway plays a key role in diverse gene expressions responsible for protection against oxidative stress and xenobiotics. Chalcones with a common chemical scaffold of 1,3-diaryl-2- propen-1-one, are abundantly present in nature with a wide variety of pharmacological properties. This review will discuss the interactions of natural and synthetic chalcones with Nrf2 signaling.

Areas covered:

Chalcones are reportedly found to activate Nrf2 signaling pathway, expression of Nrf2-regulated antioxidant genes, induce cytoprotective proteins and upregulate multidrug resistance-associated proteins. Chalcones being soft electrophiles are less prone to hostile off-target effects and unlikely to induce carcinogenicity and mutagenicity. Furthermore, their low toxicity, structural diversity, feasibility in structural reorganization and the presence of α,β-unsaturated carbonyl group which makes them suitable drug candidates targeting Nrf2-dependent diseases.

Expert opinion:

Nrf2-Keap1 signaling pathway plays a central role in redox signaling. However, available therapeutic agents for Nrf2 activation have limited practical applications due to their associated risks, relatively low efficacy and bioavailability. The designing and fabrication of new chemical entities with chalcone scaffold-based Michael acceptor mechanism should be aimed as potential therapeutic Nrf2 activators to target oxidative stress and inflammation-mediated diseases such as atherosclerosis, Parkinson’s disease and many more.

KEYWORDS:

• Antioxidant
• Nrf2
• chalcone
• keap1
• Michael acceptor mechanism

Article highlights

• Nrf2-Keap1 signaling pathway is a key driver in redox signaling and inflammation, therefore, a correct approach is needed in the evaluation of the chemical entities as Nrf2 modulators.

• Despite the advancement in research focused on inflammation, most compounds are still in clinical trials and only dimethyl fumarate is currently approved as Nrf2 activator in multiple sclerosis.

• Chalcone scaffold (1,2-diphenyl-2-propen-1-one), abundantly present in nature, have shown promising results for Nrf2 activation.

• Chalcones act as Michael acceptors and readily react with the cysteine residues of proteins.

• In this paper, we reviewed the mechanisms and structure activity relationships of chalcones as potential therapeutic agents targeting Nrf2-dependent diseases.

• Our review will improve the understanding for designing and synthesis of novel compounds with chalcone scaffold as Nrf2 activators.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded.