Engineering piperlongumine-inspired analogs as Nrf2-dependent neuroprotectors against oxidative damage by an electrophilicity-based strategy

Oxidative stress contributes significantly to the development of neurodegenerative diseases, thus developing nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent neuroprotectors is highly required for either pre-vention or treatment of these diseases. This work highlights an electrophilicity-based strategy that allows finding more active Nrf2-dependent neuroprotectors than natural piperlongumine (PL). Electrophilic modification was applied on both the exocylic and endocyclic Michael acceptors of PL, which includes placement of an electron-withdrawing trifluoromethyl group on its aromatic ring in the ortho, meta, or para position to the exocyclic olefin, and further introduction of an electron-withdrawing alpha-chlorine on its lactam ring. From a panel of PL analogs, we identified PLCl-4CF3, characterized by the presence ofp-trifluoromethyl group and alpha-chlorine, to be significantly superior to the parent PL in protecting PC12 cells from oxidative damage induced by 6-hydroxydopamine hy-drochloride. Mechanistic studies reveal that the increased electrophilicity of PLCl-4CF3 in its two Michael ac-ceptors allows its ability to covalently modify Cys-151 at Keap1, facilitating inhibition against Nrf2 ubiquitination, translocation of Nrf2 into the nucleus, induction of phase 2 enzymes and final protection of PC12 cells from oxidative damage.

Automated summary

Oxidative stress plays a significant role in neurodegenerative diseases. Therefore, developing Nrf2-dependent neuroprotectors is crucial for prevention and treatment. This study utilized an electrophilicity-based strategy to find more active neuroprotectors than natural piperlongumine (PL).