gamma-mangostin and mangostin

MutT homologue 1 (MTH1) protects the nucleotide pool from oxidative stress by hydrolyzing oxidized nucleoside triphosphates and prevents their incorporation into DNA. Cancer cells are dependent on the MTH1 activity for survival due to the high-level of reactive oxygen species in cancer cells; therefore, MTH1 is considered to be a novel target for treatment of various cancers. Here, we show by X-ray crystallographic screening using an in-house cocktail library that α-mangostin, a natural xanthone from mangosteen pericarp, binds to the active site of MTH1. A subsequent inhibition assay revealed that 3-isomangostin, a cyclized derivative of α-mangostin, was the most potent MTH1 inhibitor, with an IC

Topics: Catalytic Domain; Crystallography, X-Ray; DNA Repair Enzymes; Drug Discovery; Drug Evaluation, Preclinical; Enzyme Inhibitors; Garcinia mangostana; Phosphoric Monoester Hydrolases; Protein Binding; Xanthones

Topics: alpha-Glucosidases; Clusiaceae; Enzyme Assays; Enzyme Inhibitors; Glycoside Hydrolase Inhibitors; Humans; Inhibitory Concentration 50; Kinetics; Magnetic Resonance Spectroscopy; Molecular Conformation; Plant Roots; Protein Binding; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Xanthones

Somatic heterozygous mutations of isocitrate dehydrogenase-1 (IDH1) are abundantly found in several types of cancer and strongly implicate altered metabolism in carcinogenesis. In the present study, we have identified α-mangostin as a novel selective inhibitor of mutant IDH1 (IDH1-R132H). We have observed that α-mangostin competitively inhibits the binding of α-ketoglutarate (α-KG) to IDH1-R132H. The structure-relationship study reveals that α-mangostin exhibits the strongest core inhibitor structure. Finally, we have observed that α-mangostin selectively promotes demethylation of 5-methylcytosine (5mC) and histone H3 trimethylated lysine residues in IDH1 (+/R132H) MCF10A cells, presumably via restoring the activity of cellular α-KG-dependent DNA hydroxylases and histone H3 lysine demethylases. Collectively, we provide evidence that α-mangostin selectively inhibits IDH1-R132H.

Topics: Binding, Competitive; Drug Discovery; Humans; Isocitrate Dehydrogenase; MCF-7 Cells; Molecular Structure; Mutation; Recombinant Proteins; Structure-Activity Relationship; Xanthones

A xanthone-derived natural product, α-mangostin is isolated from various parts of the mangosteen, Garcinia mangostana L. (Clusiaceae), a well-known tropical fruit. Novel xanthone derivatives based on α-mangostin were synthesized and evaluated as anti-cancer agents by cytotoxicity activity screening using 5 human cancer cell lines. Some of these analogs had potent to moderate inhibitory activities. The structure-activity relationship studies revealed that phenol groups on C3 and C6 are critical to anti-proliferative activity and C4 modification is capable to improve both anti-cancer activity and drug-like properties. Our findings provide new possibilities for further explorations to improve potency.

Topics: Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Garcinia mangostana; Humans; Neoplasms; Structure-Activity Relationship; Xanthones

Twelve xanthone constituents of the botanical dietary supplement mangosteen (the pericarp of Garcinia mangostana) were screened using a noncellular, enzyme-based microsomal aromatase inhibition assay. Of these compounds, garcinone D (3), garcinone E (5), alpha-mangostin (8), and gamma-mangostin (9) exhibited dose-dependent inhibitory activity. In a follow-up cell-based assay using SK-BR-3 breast cancer cells that express high levels of aromatase, the most potent of these four xanthones was gamma-mangostin (9). Because xanthones may be consumed in substantial amounts from commercially available mangosteen products, the consequences of frequent intake of mangosteen botanical dietary supplements require further investigation to determine their possible role in breast cancer chemoprevention.

Topics: Anticarcinogenic Agents; Aromatase Inhibitors; Dietary Supplements; Dose-Response Relationship, Drug; Garcinia mangostana; Molecular Structure; Xanthones

We examined the effects of six xanthones from the pericarps of mangosteen, Garcinia mangostana, on the cell growth inhibition of human leukemia cell line HL60. All xanthones displayed growth inhibitory effects. Among them, alpha-mangostin showed complete inhibition at 10 microM through the induction of apoptosis.

Topics: Apoptosis; Blotting, Western; Garcinia; HL-60 Cells; Humans; Indonesia; Inhibitory Concentration 50; Leukemia; Molecular Structure; Plants, Medicinal; Stereoisomerism; Tumor Cells, Cultured; Xanthones