Eleusenticosides A–O: Neuroprotective Triterpenoid Saponins from the Leaves of <i>Eleutherococcus senticosus</i> Using a Building-Block-Based Molecular Networking Strategy

Twenty-two oleanane-type triterpenoid saponins were isolated from the ethanol-extract of <i>Eleutherococcus senticosus</i> leaves through building-block-based molecular-networking-guided strategy, among which 15 new compounds, eleusenticosides A-O (<b>1</b>-<b>15</b>), were isolated and identified. Notably, eleusenticosides A and B (<b>1</b>, <b>2</b>) containing eight sugar units were the largest saponins that have been discovered from <i>E. senticosus</i> so far. The structural elucidation was achieved using comprehensive spectroscopic techniques, including 1D/2D NMR and HRESIMS, complemented by acid hydrolysis. Furthermore, the neuroprotective potential of these saponins was evaluated in an Aβ_25-35-induced neurite degeneration primary neuron model. The results revealed that saponins <b>3</b>, <b>5</b>, <b>17</b> and <b>19</b> can significantly restrain the axonal damage and promote neuronal network regeneration, suggesting their potential as therapeutic candidates for neurodegenerative diseases. A structure-activity relationship analysis mainly revealed that the neuroprotectivity of saponins might be affected mainly by the noroleanane-type aglycone and specific sugar units.