Screening of novel VEGFR-2-targeting sesquiterpenes from Lindera aggregata and anti-angiogenesis assay

As one of the key secondary metabolites from plants, sesquiterpenoids exhibit significant promise for treating various diseases owing to their extensive structural diversity and remarkable pharmacological activities. In recent years, vascular endothelial growth factor receptor 2 (VEGFR-2) has attracted considerable interest as a critical target for anticancer drug development. This study conducted a systematic chemical analysis of Lindera aggregata (Sims) Kosterm. (Lauraceae), a species rich in sesquiterpenoid constituents. Of the 14 sesquiterpenoids that were isolated, compounds 1-8 were found to be undescribed. The results of affinity ultrafiltration mass spectrometry (AUF-MS) screening suggested that compounds 1, 3, 4, 6, and 12-14 demonstrated binding affinity for VEGFR-2. Further molecular docking simulation revealed that the binding free energies of these compounds with VEGFR-2 (PDB ID: 2OH4) ranged from -7.2 to -8.2 kcal/mol, suggesting their potential anti-angiogenesis activity. Subsequent evaluation demonstrated the angiogenesis inhibitory effects of compound 3in vivo and in vitro. This research provided a theoretical foundation for screening natural products with anti-tumor activity and identified potential lead compounds for developing novel anticancer drugs.