Fisetin derivatives exhibit enhanced anti-inflammatory activity and modulation of endoplasmic reticulum stress

Abstract

Fisetin (FST) is a dietary flavonol that is known to possess multiple relevant bioactivities, raising the question of its potential health benefits and even its use in novel pharmacological approaches. To attain this prospect, some limitations to this molecule, namely its poor bioavailability and solubility, must be addressed. Inflammation and endoplasmic reticulum (ER) stress are often hand in hand in the context of chronic disease. Both are activated upon perceived disturbances in homeostasis but can be deleterious when intensely or chronically activated. We have synthesized a set of FST derivatives trying to improve the biological properties of the parent molecule. These new molecules were tested along with the original compound for their ability to mitigate the activation of these signaling pathways. FST has proven to be effective against the onset of inflammation, reducing NF-κB activation, cytokine release, inflammasome activation and ROS generation, as well as decreasing the activation of the unfolded protein response (UPR). Some of the tested derivatives are also described as new caspase-1 inhibitors, being also capable of reducing pro-inflammatory cytokines and ER stress markers.