Highly oxidized and rearranged schinortriterpenoids with neuroprotective activity from the stems and leaves of Schisandra chinensis

The stems and leaves (SCSL) are the main byproducts of the Schisandra chinensis cultivation process, and they are worthy of research and utilization from the perspective of medicine and economic benefits. Eighteen (1−18) undescribed highly oxygenated and rearranged schinortriterpenoids (SNTs) and six analogues (19−24), including 14(13→12):16(17→13)-diabeoschiartane (1−7), 18(13→14)-abeoschiartanes (8−12, 19), 18-norschiartane (13), schiartanes (14, 20), 16,17-secopreschisanartanes (15−17, 21−24), lancifoartane (18) skeletons, were isolated from the SCSL. Compounds 1−7 feature a rare 7/5/5-fused carbocyclic core. The structures were established by MS, NMR, single-crystal X-ray diffraction, ECD, and biogenetic considerations. In addition, neuroprotective assays were performed to gain a preliminary understanding of their biological activity. Compounds 2, 6, and 7 showed strong neurite outgrowth-promoting activity with 13.1%, 12.0%, and 12.2% cell differentiation rate (positive group: 15.4%), respectively. Compounds 1, 2, and 11 at a concentration of 25 μM also had neuroprotective effect on corticosterone (CORT)-induced PC12 cell injury, the cell viability was increased by 21.1%, 19.5%, and 24.4% (positive group: 30.6%), respectively. Molecular docking analysis and protein-protein interaction (PPI) network revealed that compounds 2, 6, and 7 can exert neuroprotective effects through the regulation of growth factor receptor-bound protein 2 (GRB2). The discovery was beneficial to the high-value utilization of SCSL and the development of natural neuroprotective drugs.