Schinortriterpenoids with an Unprecedented Oxatricyclo[4.2.1.04,8]nonane Bridged System from Schisandra chinensis

Six new schinortriterpenoids (SNTs), including one structurally unique SNT featuring a caged oxatricyclo[4.2.1.04,8]nonane bridged system (1) and five previously undescribed SNTs (2−6), were isolated from the fruits of Schisandra chinensis. The structures and configurations of compounds 1−6 were elucidated via comprehensive spectroscopic analysis, nuclear magnetic resonance (NMR) calculations, DP4+ analysis, electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction. All compounds were evaluated for their neuroprotective activity against H2O2-induced injury in PC12 cells, and compound 1 exhibited potent neuroprotective activity, with an EC50 value of 1.02 ± 0.18 μM. Nuclear receptor subfamily 3 group C member 2 (NR3C2) was identified as a potential target through which compound 1 exerts its neuroprotective effect through virtual screening, molecular dynamics (MD) simulation, and experimental validation. The discovery of compound 1 broadens the chemical diversity of known SNTs and provides a novel bioactive scaffold for natural product development.