Rutaecarpine derivatives synthesized <i>via</i> skeletal reorganization alleviate inflammation-associated oxidative damage by inhibiting the MAPK/NF-κB signaling pathway

In recent years, skeleton reorganization based on bioactive natural products has emerged as a novel alternative strategy to the classical approach, mainly focusing on the peripheral modification of the inherent natural skeleton. Such reorganizations not only afford structurally unique molecules but also provide unanticipated bioactivities compared with the unaltered natural precursors. Herein, by rebuilding the inherent rigid skeleton of cardioprotective rutaecarpine (RUT), thirty-three structural derivatives were designed and synthesized, with 5Ci being the most representative example, which exhibited superior protective effects against inflammation-induced ROS accumulation and cellular damage compared with the clinically used anti-inflammation drug indomethacin.