Affinity-guided discovery of natural caged xanthones and other constituents from Garcinia oligantha as VEGFR-2 inhibitors with anti-angiogenic activity

초록

Cancer poses a significant threat to human health, and vascular endothelial growth factor receptor 2 (VEGFR-2), a key mediator in tumor-driven angiogenesis, has emerged as a highly promising therapeutic target for anticancer drug development. Xanthones, with their multiple structures and biological properties, are an excellent source of anti-cancer medications. In this study, we employed affinity ultrafiltration-mass spectrometry (AU-MS) combined with systematic phytochemical exploration to discover VEGFR-2-targeting constituents with antiangiogenic activity from Garcinia oligantha, a medicinal plant known for its richness in xanthones. A total of 26 compounds, including six caged xanthones (1-6) and one rearranged xanthone derivative (7), were purified from Garcinia oligantha. The chemical structures of these isolates were rigorously characterized through comprehensive spectroscopic analysis, comprising NMR, HRESIMS, and ECD data. To rapidly identify potential bioactive molecules, an affinity ultrafiltration-ultra performance liquid chromatography-mass spectrometry (AUUPLC-MS) screen was employed using VEGFR-2 as the target protein. This approach revealed that ten of the isolated compounds exhibited significant binding affinity to VEGFR-2. Subsequent molecular docking studies corroborated these findings, showing that the active compounds interacted with the target protein primarily through hydrogen bonding and hydrophobic interactions, with predicted binding strengths varying between -7.1 to -9.3 kcal/mol. The anti-angiogenetic potential was further validated using a transgenic zebrafish model, and compound 1 demonstrated significant inhibitory activity against vessel formation. These results highlighted the potential of these xanthones as novel antitumor candidates acting via VEGFR-2 inhibition and underscore the pharmacological value of G. oligantha.

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