In Vivo Screening of Xanthones from Garcinia oligantha Identified Oliganthin H as a Novel Natural Inhibitor of Convulsions.

Epilepsy is a chronic neurological disorder, characterized by recurrent, spontaneous, and transient seizures, and affects more than 70 million people worldwide. Although two dozen antiepileptic drugs (AEDs) are approved and available in the market, seizures remain poorly controlled in one-third of epileptic patients who are suffering from drug resistance or various adverse effects. Recently, the xanthone skeleton has been regarded as an attractive scaffold for the discovery and development of emerging anticonvulsants. We had isolated several dihydroxanthone derivatives previously, including oliganthin H, oliganthin I, and oliganthin N, whose structures were similar and delicately elucidated by spectrum analysis or X-ray crystallographic data, from extracts of leaves of Garcinia oligantha. These xanthone analogues were evaluated for anticonvulsant activity, and a novel xanthone, oliganthin H, has been identified as a sound and effective natural inhibitor of convulsions in zebrafish in vivo. A preliminary structure-activity relationship analysis on the relationship between structures of the xanthone analogues and their activities was also conducted. Oliganthin H significantly suppressed convulsant behavior and reduced to about 25% and 50% of PTZ-induced activity, in 12.5 and 25 µM treatment groups (P < 0.01 and 0.001), respectively. Meanwhile, it reduced seizure activity, velocity, seizure duration, and number of bursts in zebrafish larvae (P < 0.05). Pretreatment of oliganthin H significantly restored aberrant induction of gene expressions including npas4a, c-fos, pyya, and bdnf, as well as gabra1, gad1, glsa, and glula, upon PTZ treatment. In addition, in silico analysis revealed the stability of the oliganthin H-GABAA receptor complex and their detailed binding pattern. Therefore, direct interactions with the GABAA receptor and involvement of downstream GABA-glutamate pathways were possible mechanisms of the anticonvulsant action of oliganthin H. Our findings present the anticonvulsant activity of oliganthin H, provide a novel scaffold for further modifications, and highlight the xanthone skeleton as an attractive and reliable resource for the development of emerging AEDs.

Xanthone derivatives from the leaves of Garcinia oligantha.

Nine new and unique xanthone derivatives, including one novel hybrid monoterpene-tetrahydroxanthone (1), three dihydro-xanthone derivatives (2-4), and five skeleton-rearranged xanthone derivatives (5-9), were obtained from a 95% EtOH extract of Garcinia oligantha leaves by a LC-MS-guided fractionation procedure. The structures of the new compounds were elucidated by analysis of their 1D and 2D NMR and MS data. The relative configurations of 2 and 8 were determined via X-ray crystallographic data analysis, while the absolute configurations of 1-2, 5-9 were assigned based on a comparison of calculated and experimental ECD and/or OR data. In SRB, PI-exclusion and Hoechst staining assays, 6 showed strong cytotoxic activities which could dose-dependently induce Taxol-insensitive quiescent LNCaP cell death. Additionally, a preliminary mechanism investigation using immunoblotting and Caspase-3 activity assay, indicated that 6 induced quiescent LNCaP cell death potentially through caspase-dependent mitochondrial apoptosis pathway.

Bioassay-Guided Isolation of Prenylated Xanthone Derivatives from the Leaves of Garcinia oligantha.

Four new dihydroxanthone derivatives (1-4), four new tetrahydroxanthone derivatives (5-8), two new xanthone derivatives (9 and 10), and two known caged tetrahydroxanthones were isolated from extracts of the leaves of Garcinia oligantha by bioassay-guided fractionation. These structures of the new compounds were elucidated by NMR and MS spectroscopic data analysis, and the absolute configurations of compounds 1 and 5-7 were determined by electronic circular dichroism and/or single-crystal X-ray diffraction analysis. Compounds 6-9 were shown to be unusual xanthone derivatives with an isopropyl group, which was confirmed by the X-ray crystallographic structure of compound 8. The inhibitory activities of these isolates against four human tumor cell lines (A549, HepG2, HT-29, and PC-3) were assayed, and compounds 1, 2, 5, 11, and 12 showed inhibitory effects on tumor cell growth, with IC50 values ranging from 2.1 to 8.6 µM.