Abstract
Developing nuclear factor erythroid-2 related factor 2 (Nrf2)-dependent cytoprotectors against oxidative damage is of concern because they can effectively reduce the risk of oxidative stress-related diseases, such as cancer and inflammation. This work was aimed to develop more active Nrf2-dependent cytoprotectors than curcumin, a well-known dietary Nrf2 activator and cancer chemopreventive agent. Herein we designed a panel of curcumin-inspired mono-carbonyl piperidinone analogs differentiated by placing distinct electron-withdrawing and electron-donating groups on its two aromatic rings in the ortho, meta, or para position to the linker of α, β-unsaturated piperidinone. Among these, the ortho-fluorine-substituted CN-2F surfaced as a promising lead molecule, which was significantly superior to the parent curcumin in protecting HepG2 cells from oxidative damage induced by tert-butyl hydroperoxide. Mechanically, by virtue of its Michael receptor units and ortho-substituted mode, CN-2F activated Nrf2 signaling by covalently modifying Cys-151 and Cys-288 residues at Keap1, promoting phosphorylation of JNK, ERK and p38, as well as inhibiting Nrf2 degradation. This work reveals the structural determinants and the activity mechanisms of CN-2F as an Nrf2-dependent cytoprotector, and gives useful information on how to design curcumin-inspired Nrf2 activators and cytoprotectors.