Affinity-guided discovery of dimeric sesquiterpenes from Xylopia vielana as potent VEGFR-2 inhibitors with anti-angiogenic activity.

Natural products represent a rich source for the discovery of novel therapeutic agents. In our ongoing search for bioactive natural compounds, the chemical constituents of Xylopia vielana twigs were investigated. Chromatographic separation techniques, including silica gel chromatography, medium pressure liquid chromatography (MPLC), and semi-preparative high performance liquid chromatography (HPLC), applied to the methanol extract of X. vielana twigs, coupled with extensive spectroscopic analysis (HRESIMS, NMR, ECD, IR, and DP4+ calculations), led to the isolation and identification of 12 guaiane-type sesquiterpenoids. Among these, nine compounds (1-9) are reported herein as novel guaiane-type sesquiterpene dimers, while three (10-12) were identified as known sesquiterpenoid monomers. To evaluate their potential anti-angiogenic activity, the isolated compounds were initially subjected to affinity screening against vascular endothelial growth factor receptor 2 (VEGFR-2). Compounds exhibiting significant affinity were further investigated through molecular docking studies to predict their binding modes and interaction sites. Promising candidates were subsequently assessed for anti-angiogenic effects in vivo using a transgenic zebrafish model (Tg(fli1:EGFP)). Compound 9 demonstrated notable anti-angiogenic activity in the zebrafish model, suggesting its potential as a VEGFR-2 inhibitor.