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

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 alpha,beta-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.

Automated summary

The Nrf2 signaling pathway is important for protecting the body from oxidative stress and xenobiotics. Chalcones, which are compounds with a common chemical structure of 1,3-diaryl-2-propen-1-one, have various pharmacological properties and can activate the Nrf2 signaling pathway. They are considered to be potential drug candidates for targeting Nrf2-dependent diseases due to their low toxicity, structural diversity, and ability to upregulate protective proteins.