Caged xanthones with cytotoxic activity from the leaves and twigs of Garcinia oligantha

Abstract

Phytochemical studies on the leaves and twigs of Garcinia oligantha led to the isolation of the previously undescribed caged xanthones including two pairs of enantiomers (±) oliganthxanthone A (1a, 1b), (±) oliganthxanthone B (2a, 2b), (-) 15-hydroxy-8,8a-dihydrogaudichaudione H (3), and (-) 2-geranyl-gaudichaudione H (4), and fourteen known analogues (5-16, 17a, and 17b). Their structures were established by HRMS, NMR spectroscopic analysis, and ECD calculation. Notably, 1 and 2 featuring the unprecedented 10,10-dimethyl-4-oxa-tricyclo[4.3.1.0^3,7]dec-2-one scaffold, were rare scalemic caged polyprenylated xanthones (CPXs) different from the previously described CPXs with 5,5-dimethyl-4-oxa-tricyclo[4.3.1.0^3,7]dec-2-one unit. This indicated the presence of two emerging biosynthetic pathways, highlighting the exploration of uncharted biochemical routes. A plausible biosynthetic pathway of these compounds was proposed. The cytotoxic activities of all the isolated compounds against A375 (human malignant melanoma cells), A549 (human lung adenocarcinoma cells), HepG2 (human hepatocellular carcinoma cells), and MCF-7 (human breast adenocarcinoma cells) were assayed. Among all the undescribed compounds, 4 showed the strongest cytotoxic activity. Further research revealed that 4 exerted its cytotoxic activity by promoting cell apoptosis, and it also exhibited anti-migratory and anti-invasive activities against A549 and MCF-7 cells. Network pharmacology analysis and molecular docking experiments indicated that 4 was likely to induce apoptosis in MCF-7 cells by acting on the NF-κB pathway through IKKβ protein.