Xanthone

The twigs of Calophyllum inophyllum

Xanthone shows the antagonism of endogenous nitric oxide synthase (NOS) inhibitors, it has antitumor, antihepatotoxic, anti-inflammatory and antimicrobial activities [1]. Two derivatives of xanthone potently inhibited nitric oxide synthesis with IC50 values of 4.3 and 4.4 μM, respectively [2].

In endothelial cells, NOS synthesizes nitric oxide (NO) from L-arginine. In the maintenance of vascular structure and tone, NO has been thought to play a key role [1].

Asymmetric dimethylarginine (ADMA) is synthesized by protein arginine methyltransferases (PRMTs), using S-adenosylmethionine as methyl group donor. Dimethylarginine dimethylaminohydrolase (DDAH) degrades ADMA to L-citrulline and dimethylamine. There are two different isoforms of DDAH, DDAH-1 and DDAH-2. Typically, DDAH-1 is found in tissues containing neuronal NOS, whereas DDAH-2 predominates in tissues expressing the endothelial isoform of NOS. In cultured endothelial cells, xanthones showed the inhibition of the upregulation of MCP-1 expression, the enhancement of monocytes adhesion and the increase in the release of LDH, concomitantly with the reduction of ADMA levels. These results suggest that xanthones protect against high-lipid-level-induced endothelial damage. This protective effect of xanthones is related to the reduction of ADMA concentration [1].

A single injection of native LDL caused a rapid accumulation and oxidation of LDL in the arterial wall. At 6 to 12 h after injection of LDL, ICAM-1 expression increased and led to endothelial dysfunction and an elevation of ADMA level. In vivo, pretreatment with xanthones attenuated the effect of the injection of LDL [1].

References:
[1].  Jiang DJ, Dai Z and Li YJ. Pharmacological effects of xanthones as cardiovascular protective agents. Cardiovasc Drug Rev, 2004, 22(2):91-102.
[2].  Boonnak N, Khamthip A, Karalai C, et al. Nitric Oxide Inhibitory Activity of Xanthones from the Green Fruits of Cratoxylum formosum ssp. pruniflorum. Australian Journal of Chemistry, 2010, 63(11):1550-1556.

Benzophenones and xanthone derivatives from Garcinia schomburgkiana-induced P-glycoprotein overexpression in human colorectal Caco-2 cells via oxidative stress-mediated mechanisms.[Pubmed:28314481]

Phytomedicine. 2017 Apr 15;27:8-14.

BACKGROUND: Up-regulation of P-gp is an adaptive survival mechanism of cancer cells from chemotherapy. Three new phytochemicals including two benzophenones, guttiferone K (GK) and oblongifolin C (OC), and a Xanthone, isojacaruebin (ISO), are potential anti-cancer agents. However, the capability of these compounds to increase multidrug-resistance (MDR) through P-gp up-regulation in cancer cells has not been reported. PURPOSE: This study was to investigate the effects of GK, OC and ISO on P-gp up-regulation in colorectal adenocarcinoma cells (Caco-2 cells). In addition, the mechanisms underlying their inductive effect were also determined. METHODS: The inductive effect of GK, OC and ISO on P-gp expression at transcription level was measured by real-time reverse transcription polymerase chain reaction. The reactive oxygen species production was determined by 2', 7'-dichlorofluorescin diacetate assay. The protein content of P-gp and involvement of mitogen-activated protein kinases (MAPK) pathway was evaluated by western blot analysis. RESULTS: GK, OC and ISO (50 microM, 24 h) were able to increase the amount of MDR1 mRNA and protein in Caco-2 cells. The presence of N-acetyl-l-cysteine significantly prevented the inductive effect of GK, OC and ISO on MDR1 mRNA level. Moreover, MAPK inhibitors including U0126 (an ERK1/2/MAPK inhibitor) and SB202190 (p38/MAPK inhibitor) suppressed an increase of MDR1 mRNA levels in the cells treated with benzophenones (GK, OC) and Xanthone ISO, respectively. These findings were in agreement with the increase of phosphorylated form of either ERK1/2 (p-ERK1/2) or p38 (p-p38) upon treatment of the cells with these three compounds. In addition, OC and ISO, but not GK, increased mRNA of c-Jun level. CONCLUSION: The benzophenones GK, OC and Xanthone ISO are likely MDR inducers through up-regulation of P-gp expression at transcription level. Their molecular mechanisms involve oxidative stress-mediated activation of MAPK signaling pathway.

Large-Scale Preparation of a Specific Xanthone from Swertia mussotii and Evaluation of Its alpha-Glucosidase Inhibitory Activity.[Pubmed:28334929]

J Chromatogr Sci. 2017 Jul 1;55(6):638-644.

Large-scale preparation and alpha-glucosidase inhibitory activity of a specific Xanthone swertioside from Swertia mussotii were investigated in this study. Firstly, an efficient method was successfully established by liquid-liquid extraction, preparative high-performance liquid chromatography and sephadex LH-20 for large-scale preparation of swertioside. The recovery of swertioside reached 92.0%. Secondly, in vitro alpha-glucosidase inhibition experiment showed that swertioside had good inhibition close to acarbose. The study showed that swertioside had potential use as an anti-diabetic agent.

Penixanthones A and B, two new xanthone derivatives from fungus Penicillium sp. SYFz-1 derived of mangrove soil sample.[Pubmed:28299980]

Nat Prod Res. 2017 Oct;31(19):2218-2222.

Two new Xanthone derivatives, peniXanthones A (1) and B (2), together with three known compounds, aspenicillide (3), 1,5-dihydroxy-3-methoxy-7-methyl-anthracene-9,10-dione (4) and 1,2-indandiol (5), were isolated from the ethyl acetate extract of a culture of the fungus Penicillium sp. SYFz-1, which was separated from a mangrove soil sample. The structures of these compounds were elucidated by spectroscopic methods including NMR and mass spectrometry. The absolute configurations of peniXanthones A (1) and B (2) were determined on the basis of electronic circular dichroism (ECD) data analysis.

Synthesis of xanthone derivatives and studies on the inhibition against cancer cells growth and synergistic combinations of them.[Pubmed:28376372]

Eur J Med Chem. 2017 Jun 16;133:50-61.

34 Xanthones were synthesized by microwave assisted technique. Their in vitro inhibition activities against five cell lines growth were evaluated. The SAR has been thoroughly discussed. 7-Bromo-1,3-dihydroxy-9H-xanthen-9-one (3-1) was confirmed as the most active agent against MDA-MB-231 cell line growth with an IC50 of 0.46 +/- 0.03 muM. Combination of 3-1 and 5,6-dimethylXanthone-4-acetic acid (DMXAA) showed the best synergistic effect. Apoptosis analysis indicated different contributions of early/late apoptosis and necrosis to cell death for both monomers and the combination. Western Blot implied that the combination regulated p53/MDM2 to a better healthy state. Furthermore, 3-1 and DMXAA arrested more cells on G2/M phase; while the combination arrested more cells on S phase. All the evidences support that the 3-1/DMXAA combination is a better anti-cancer therapy.

Xanthone is isolated from Mangosteen and is known to control cell division and growth, apoptosis, inflammation, and metastasis in different stages of carcinogenesis. Xanthone has anti-oxidant, anti-tumor, anti-allergic, anti-inflammatory, anti-bacterial, anti-fungal, and anti-viral activities.

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