Caged Xanthones Research Articles

Activity of the Caged Xanthone Morellic Acid against Vancomycin-Resistant Enterococcus Infection by Targeting the Bacterial Membrane.

Vancomycin-resistant Enterococcus (VRE) is an important nosocomial opportunistic pathogen that is associated with multidrug resistance. Here, we demonstrate that morellic acid inhibits VRE by restoring its sensitivity to vancomycin and ampicillin with low drug resistance and efficient biofilm clearance effects. Morellic acid binds to inner membrane phospholipids, such as phosphatidylethanolamine (PE), phosphatidylglycerol (PG), and cardiolipin (CL) of VRE, such that the fluidity and proton-motive force (PMF) interfere with the damaged inner membrane, causing intracellular reactive oxygen species (ROS) accumulation and bacterial death. Transcriptional analyses supported this effect on inner membrane-related pathways such as fatty acid biosynthesis and glycerophospholipid metabolism. Moreover, morellic acid significantly eliminated residual bacteria in the spleen, liver, kidneys, and abdominal effusion in mice. Our findings indicate the potential applications of morellic acid as an antibacterial agent or adjuvant for treating VRE infections.

Antimalarial activity of caged xanthone isolated compounds from Cratoxylum sumatranum stem bark: In vitro and in silico approaches

Antimalarial activity of caged xanthone isolated compounds from Cratoxylum sumatranum stem bark: In vitro and in silico approaches

In silico Investigation of Caged Xanthone Compounds Isolated from Cratoxylum sumatranum Stem Bark against Entamoeba histolytica Enzymes

Background: Amoebiasis is caused by Entamoeba histolytica, a pathogenic species living on human colon tissues. Metronidazole is currently used for the treatment of amoebiasis, but resistance of E. histolytica to the use of such treatment has been reported. Therefore, the development of new anti-amoebic drugs is still very much needed for clinical treatment. Preliminary research on extract and fractions from Cratoxylum sumatranum stem bark has shown their anti-amoebic activity. Two compounds from the cage xanthone groups, cochinchinoxanthone and cochinchinone D, have been isolated from the active fraction of C. sumatranum stem bark. Objective: This study aimed to investigate the anti-amoebic activity of the two known compounds against E. histolytica. Methods: The in silico method used was molecular docking with several receptors, including thioredoxin reductase, triose phosphate isomerase, pyruvate ferredoxin oxidoreductase, Giardia fructose-1,6-bisphosphate aldolase, serine acetyltransferase, and phosphoserine phosphatase. The prediction of ADMET properties was also carried out for both the compounds. Results: The results showed cochinchinone D to have a higher binding affinity to thioredoxin reductase, pyruvate ferredoxin oxidoreductase, and Giardia fructose-1,6-bisphosphate aldolase receptors than cochinchinoxanthone. In contrast, cochinchinoxanthone bound better to the triose phosphate isomerase and phosphoserine phosphatase receptors, while both exhibited the same affinity for serine acetyltransferase. In general, the two compounds were also found to have similar ADMET profiles. Conclusion: In conclusion, caged xanthone compounds from C. sumatranum have the potential to be developed as anti-amoebic agents against E. histolytica through the mechanism of inhibition of these enzymes.

Caged xanthone derivatives to promote mitochondria-mediated apoptosis in breast cancer cells

Caged xanthones represent a class of natural secondary metabolites exhibiting significant potential as antitumor agents. These compounds are characterized by their distinct cage-like structures, which offer novel and compelling frameworks for drug design. Nonetheless, there exists a dearth of research focused on the structural modification of these compounds, particularly in relation to their cage-like architectures. This study aims to address this gap by introducing an innovative synthetic method for constructing a novel caged structure that incorporates a widely employed maleimide group. Drawing upon the well-established synthetic approach for dihydroxanthones previously developed within our research group, we successfully synthesized 13 new caged xanthones using the Diels-Alder reaction. Subsequently, we evaluated their anti-proliferative activity against HepG2, A549, and MDA-MB-231 cell lines. The results revealed that compound 10i exhibited IC50 values of 15.86 µM ± 1.29, 19.27 µM ± 1.58, and 12.96 µM ± 0.09 against these cell lines, respectively. Further investigations into the mechanism of action of 10i demonstrated its ability to induce G2/M cell cycle arrest and initiate mitochondria-mediated apoptosis in breast cancer cells.

Advances in Breast Cancer Drug Discovery: A Review of Therapeutic Strategies and Studies Involving Photosensitizers, Caged Xanthones and Thiosemicarbazones Derivatives

Cancer is one of the major causes of death worldwide, and breast cancer is the most prevalent and deadly type among women. Despite the side effects and the phenomena of chemoresistance associated with the drugs involved, chemotherapy remains the main therapeutic strategy to combat and control breast cancer. Therefore, several new classes of compounds against breast cancer have been explored, in an effort to identify new drug candidates with alternative mechanisms of action. The principal results of such exploration, focusing on caged xanthones, thiosemicarbazones and photosensitizers, are presented in this review, along with the main aspects of the drug discovery process against breast cancer. More specifically, the design, structure-activity relationship investigations and anti-breast cancer properties of these three classes are described and discussed in this work.

Daldipyrenones A-C: Caged [6,6,6,6,6] Polyketides Derived from an Endolichenic Fungus Daldinia pyrenaica 047188.

Daldipyrenones A-C (1-3), three unprecedented caged xanthone [6,6,6,6,6] polyketides featuring a spiro-azaphilone unit, were discovered from an endolichenic fungus, Daldinia pyrenaica 047188. The structures of 1-3 were determined by using spectroscopic analysis and chemical derivatization. Daldipyrenones are likely derived by combining a chromane biosynthesis intermediate, 1-(2,6-dihydroxyphenyl)but-2-en-2-one, and a spiro-azaphilone, pestafolide A, via radical coupling or Michael addition to form a bicyclo[2.2.2]octane ring. Genome sequencing of the strain revealed two separate biosynthetic gene clusters responsible for forming two biosynthetic intermediates, suggesting a proposed biosynthetic pathway. Daldipyrenone A (1) exhibited significant antimelanogenic activity with lower EC50's than positive controls and moderate adiponectin-secretion promoting activity.

Gambogic acid: Multi-gram scale isolation, stereochemical erosion toward epi-gambogic acid and biological profile.

Extracted from gamboge resin, gambogic acid (GBA) is a natural product that displays a complex caged xanthone structure and exhibits promising antitumor properties. However, efforts to advance this compound to clinical applications have been thwarted by its limited availability that in turn, restricts its pharmacological optimization. We report here an efficient method that allows multigram scale isolation of GBA in greater than 97% diastereomeric purity from various sources of commercially available gamboge. The overall process includes: (a) isolation of organic components from the resin; (b) separation of GBA from the organic components via crystallization as its pyridinium salt; and (c) acidification of the salt to isolate the free GBA. We found that GBA is susceptible to epimerization at the C2 center that produces epi-gambogic acid ( epi-GBA), a common contaminant of all commercial sources of this compound. Mechanistic studies indicate that this epimerization proceeds via an ortho-quinone methide intermediate. Although the observed stereochemical erosion accounts for the chemical fragility of GBA, it does not significantly affect its biological activity especially as it relates to cancer cell cytotoxicity. Specifically, we measured similar levels of cytotoxicity for either pure GBA or an equilibrated mixture of GBA/ epi-GBA in MBA-MB-231 cells with IC50 values at submicromolar concentration and induction of apoptosis after 12 hours of incubation. The results validate the pharmacological promise of gambogic acid and, combined with the multigram-scale isolation, should enable drug design and development studies.

Determination and tissue distribution comparisons of five xanthones after orally administering crude and processed gamboge.

Caged polyprenylated xanthones are the main active ingredients isolated from the resin of Garcinia hanburyi, which has been reported to exhibit potential anticancer and anti-inflammatory activities. This study aimed to develop sensitive and specific ultra-performance liquid chromatography coupled with the triple quadrupole mass spectrometry method for investigating the tissue distribution of five xanthones in rats: β-morellic acid, isogambogenic acid, gambogenic acid, R-gambogic acid and S-gambogic acid. All tissue samples were prepared using the liquid-liquid extraction method and separated on a C8 column with a gradient system. Detection was performed on a triple quadrupole mass spectrometer in multiple-reaction monitoring using positive ionization. The method established in this assay was successfully applied to the tissue distribution study of the five selected xanthones after orally administering crude and processed gamboge in rat tissues. The results indicated that these five xanthones were distributed to rat tissues rapidly and could be detected in all of the selected tissues after oral administration. After processing, the contents of R-gambogic acid and S-gambogic acid in the gastrointestinal tract were significantly reduced. The findings of this study might be helpful in further understanding the processing mechanism of gamboge and providing references for its reasonable clinical application.

Gambogenic acid alleviates kidney fibrosis via epigenetic inhibition of EZH2 to regulate Smad7-dependent mechanism

BackgroundEpigenetics regulating gene expression plays important role in kidney fibrosis. Natural products originating from diverse sources including plants and microorganisms are capable to influence epigenetic modifications. Gambogenic acid (GNA) is a caged xanthone extracted from gamboge resin, exudation of Garcinia hanburyi Hook.f., and the effect of GNA on kidney fibrosis with its underlying mechanism on epigenetics remains unknown. PurposeThis study aimed to explore the role of GNA against kidney fibrogenesis by histone methylation mediating gene expression. MethodsTwo experimental mice of unilateral ureteral obstruction (UUO) and folic acid (FA) were given two dosages of GNA (3 and 6 mg/kg/d). TGF-β1 was used to stimulate mouse tubular epithelial (TCMK-1) cells and siRNAs were transfected to verify the underlying mechanisms of GNA. Histological changes were evaluated by HE, MASSON stainings, immunohistochemistry and immunofluorescence. Western blot and qPCR were used to measure protein/gene transcription levels. ResultsGNA dose-dependently alleviated UUO-induced kidney fibrosis and FA-induced kidney early fibrosis, indicated by the pathology and fibrotic factor changes (α-SMA, collagen I, collagen VI, and fibronectin). Mechanically, GNA reduced enhancer of zeste homolog 2 (EZH2) and H3K27me3, promoted Smad7 transcription, and inhibited TGF-β/Smad3 fibrotic signaling in injured kidneys. Moreover, with TGF-β1-induced EZH2 increasing, GNA suppressed α-SMA, fibronectin and collagen levels in tubular epithelial TCMK-1 cells. Although partially decreasing EZH2, GNA did not influence fibrotic signaling in Smad7 siRNA-transfected TCMK-1 cells. ConclusionEpigenetic inhibition of EZH2 by GNA ameliorated kidney fibrogenesis via regulating Smad7-meidated TGF-β/Smad3 signaling.

Transcriptome analysis of developing zebrafish (Danio rerio) embryo following exposure to Gaudichaudione H reveals teratogenicity and cardiovascular defects caused by abnormal iron metabolism

Gaudichaudione H (GH), a caged polyprenylated xanthone from Garcinia plants, showed anti-cancer and anti-inflammatory effects in vitro. However, the in vivo toxicity of this compound has never been reported. The present study was aimed to address the toxic effects of Gaudichaudione H using zebrafish embryos and larvae as an in vivo test model. The zebrafish embryos were treated with GH having different concentrations (0, 0.28, 0.38 and 0.57 μg/mL). The results revealed that GH induces significant embryonic mortality, decreased heartbeat, cardiotoxicity, cardiovascular defects, increased apoptosis and decreased hemoglobinization in zebrafish embryos and larvae. According to transcriptome analysis, 1841 genes were significantly differentially expressed (1185 down-regulated and 656 up-regulated) after GH treatment. The main functions of these genes were related to iron metabolism pathways. The toxicity of GH on zebrafish embryonic development and cardiovascular may due to large amounts of downregulated genes involved in metabolic pathways and DEGs related to ‘Iron ion binding’ and ‘Heme binding’ functions.

Structural diversity and biological activities of caged Garcinia xanthones: recent updates

Caged xanthones are a class of natural compounds with approximately 200 members that are commonly isolated from the Garcinia genus in the Clusiaceae (formerly Guttiferae) family. They are often characterized by a notable 4-oxa-tricyclo[4.3.1.03,7]dec-2-one (caged) architecture with a common xanthone backbone. Because most caged xanthones have potent anticancer properties, they have become a target of interest in natural product chemistry. The unique chemical architectures and increasingly identified biological importance of these compounds have stimulated many studies and intense interest in their isolation, biological evaluation and mechanistic studies. This review summarizes recent progress and development in the chemistry and biological activity of caged Garcinia xanthones and of several compounds of non-Garcinia origin, from the years 2008 to 2021, providing an in-depth discussion of their structural diversity and medicinal potential. A preliminary discussion on structure-activity relationships is also provided.

Cytotoxic 7‐Methoxylated Caged Xanthones from the Twigs of Garcinia oligantha

Main observation and conclusionNineteen unprecedented 7‐methoxylated caged xanthones (1—19) were isolated from the twigs of Garcinia oligantha under the guidance of NMR spectroscopy. Their structures and absolute configurations were demonstrated by extensive spectroscopic data, single‐crystal X‐ray diffraction, electronic circular dichroism (ECD) calculations, and the modified Mosher's method. Compound 1 is a rare scalemic 7‐methoxylated neo‐caged xanthone, which was resolved using HPLC with CD detection on a chiral‐phase AD column, and compounds 2—3 are rare 7‐methoxylated caged xanthones with the hydrogenated Δ8(8a) double bond. Fourteen compounds exhibited promising inhibitory activities against four human cancer cell lines with IC50 values ranging from 1.9 to 14.3 μmol/L. A cell apoptosis analysis using flow cytometry showed that compound 11 could induce apoptosis in a dose dependent manner. Moreover, PARP, caspase‐9, and Bcl‐2 western blotting suggested that compound 11‐induced apoptosis may be involved in caspase‐dependent pathway.

Network Pharmacology Analysis and Experimental Pharmacology Study Explore the Mechanism of Gambogic Acid against Endometrial Cancer.

Endometrial cancer (EC) is one of the three most common gynecological cancers in female groups. Gambogic acid (GA), a natural caged xanthone, exerts significantly antitumor effects on many cancers. However, its efficacy on EC and pharmacological mechanism of action remain marginal up to now. This study suggested that GA had significant inhibitory effects on EC in vitro and in vivo, and no toxicity to normal cells or mice. In detail, GA suppressed cell proliferation, induced cell apoptosis, and cell cycle arrest at G0/G1 stage, complied with the network pharmacology analysis, showed that the PI3K/Akt pathways were the most important signaling, and their protein and mRNA expression levels were confirmed by qRT-PCR and Western blot experiments. In all, our study first proved that GA could inhibit cell proliferation, induce cell apoptosis, and cell cycle arrest at G0/G1 stage via the PI3K/Akt pathways, so GA would be a good therapy for EC.

Nujiangexanthone A Inhibits Hepatocellular Carcinoma Metastasis via Down Regulation of Cofilin 1.

Hepatocellular carcinoma (HCC) is one of the malignant tumors with poor prognosis. High expression level of cofilin 1 (CFL1) has been found in many types of cancers. However, the role of CFL1 in HCC hasn’t been known clearly. Here, we found that CFL1 was up regulated in human HCC and significantly associated with both overall survival and disease-free survival in HCC patients. Nujiangexanthone A (NJXA), the caged xanthones, isolated from gamboge plants decreased the expression of CFL1, which also inhibited the migration, invasion and metastasis of HCC cells in vitro and in vivo. Down regulation of CFL1 inhibited aggressiveness of HCC cells, which mimicked the effect of NJXA. Mechanism study indicated that, knockdown of CFL1 or treatment with NJXA increased the level of F-actin and disturbed the balance between F-actin and G-actin. In conclusion, our findings reveal the role of CFL1 in HCC metastasis through the CFL1/F-actin axis, and suggest that CFL1 may be a potential prognostic marker and a new therapeutic target. NJXA can effectively inhibit the metastasis of HCC cells by down regulating the expression of CFL1, which indicates the potential of NJXA for preventing metastasis in HCC.

Natural Xanthones and Skin Inflammatory Diseases: Multitargeting Mechanisms of Action and Potential Application.

The pathogenesis of skin inflammatory diseases such as atopic dermatitis, acne, psoriasis, and skin cancers generally involve the generation of oxidative stress and chronic inflammation. Exposure of the skin to external aggressors such as ultraviolet (UV) radiation and xenobiotics induces the generation of reactive oxygen species (ROS) which subsequently activates immune responses and causes immunological aberrations. Hence, antioxidant and anti-inflammatory agents were considered to be potential compounds to treat skin inflammatory diseases. A prime example of such compounds is xanthone (xanthene-9-one), a class of natural compounds that possess a wide range of biological activities including antioxidant, anti-inflammatory, antimicrobial, cytotoxic, and chemotherapeutic effects. Many studies reported various mechanisms of action by xanthones for the treatment of skin inflammatory diseases. These mechanisms of action commonly involve the modulation of various pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor α (TNF-α), as well as anti-inflammatory cytokines such as IL-10. Other mechanisms of action include the regulation of NF-κB and MAPK signaling pathways, besides immune cell recruitment via modulation of chemokines, activation, and infiltration. Moreover, disease-specific activity contributed by xanthones, such as antibacterial action against Propionibacterium acnes and Staphylococcus epidermidis for acne treatment, and numerous cytotoxic mechanisms involving pro-apoptotic and anti-metastatic effects for skin cancer treatment have been extensively elucidated. Furthermore, xanthones have been reported to modulate pathways responsible for mediating oxidative stress and inflammation such as PPAR, nuclear factor erythroid 2-related factor and prostaglandin cascades. These pathways were also implicated in skin inflammatory diseases. Xanthones including the prenylated α-mangostin (2) and γ-mangostin (3), glucosylated mangiferin (4) and the caged xanthone gambogic acid (8) are potential lead compounds to be further developed into pharmaceutical agents for the treatment of skin inflammatory diseases. Future studies on the structure-activity relationships, molecular mechanisms, and applications of xanthones for the treatment of skin inflammatory diseases are thus highly recommended.

Prenylated xanthones and benzophenones from the fruits of Garcinia bracteata and their potential antiproliferative and anti-inflammatory activities

Ten previously undescribed compounds, including five prenylated xanthones (1–5), two caged xanthones (16–17) and three rearranged benzophenones (27–29), together with nineteen known compounds were isolated from the fruits of Garcinia bracteata. Their structures were established on the basis of spectroscopic analysis, electronic circular dichroism calculations, and X-ray crystallographic data. Compound 17 was a caged xanthone bearing a rare 8, 8a-epoxy moiety. Compound 28 belonged to the rearranged benzophenones with rare 2, 7-dioxabicyclo-[2.2.1] heptane moiety fused at C-2 and C-3 respectively. The antiproliferative and anti-inflammatory activities of all isolated compounds were evaluated. Compounds 23 and 24 exhibited remarkable inhibitory activities against three human cancer cell lines (HepG2, T98, MCF-7) with IC50 values ranging from 3.21 ± 1.00 to 6.27 ± 1.03 μM. Moreover, compounds 20 and 24 also displayed significant inhibitory effects against NO production with IC50 values of 1.22 ± 0.01 and 1.77 ± 0.23 μM respectively. These results enrich the structural diversities of xanthones and benzophenones from Garcinia plants. Neobractatin (24) due to its anti-tumor and anti-inflammatory effects is worth further investigation in anticancer research.

Antiproliferative activity of caged xanthones from the leaves of Garcinia wightii T. Anderson

Two new caged xanthones, wightiic acid (1) 16-O-methyl wightiic acid (2), along with eight known compounds, gaudichaudic acid E (3), isogaudichaudic acid E (4), ursolic acid (5) stigmasterol (6), lupeol (7), glutinol (8), lupenone (9) and stigmasteryl linoleate (10) were isolated from Garcinia wightii T. Anderson. The structures of the compounds were elucidated by spectroscopic means, including 1D and 2D NMR, HR-ESIMS, and the absolute configuration of the new compounds 1 and 2 were determined by analysis of ECD data. Anti-proliferation activities of the four caged xanthones (1–4) were evaluated by MTT assay on MCF-7 and SKBR-3 human breast cancer cells and A-375 human melanoma cells by MTT assay. All the tested compounds exhibited dose dependent antiproliferative activity. Wightiic acid (1) showed remarkable activity with IC50 value of 4.7 μM and 5.2 μM respectively in A-375 and MCF-7 cells. The compound isogaudichaudic acid E (4) induced potent antiproliferation against SKBR-3 cells with an IC50 value of 6.1 μM.

Mechanistic density functional theory study of the Claisen Rearrangement Diels-Alder Cycloaddition domino sequence for the synthesis of the caged garcinia xanthone

Abstract The mechanism of the tandem Claisen-Rearrangement-Diels-Alder-Cycloaddition reactions of the caged garcinia xanthone derivatives has been investigated and optimized by density functional theory (DFT) calculations studies at the B3LYP/6-31G+(d) level of theory. Hence, this study attempts to exploit and to show the favored reaction path leads in the step of a Claisen-Rearrangement-Diels-Alder-Cycloaddition reaction and to determinate the thermodynamic and kinetic products. For this purpose, an energy profile was determined by the optimization of the geometries of reactants, products and the corresponding transition-state (TS). The intrinsic reaction coordinate (IRC) analyses were made. Fukui functions, electrostatic potential surfaces and HOMO-LUMO energy of the component 1-O-methyl forbesione 1 were computed at the same level of theory. The Hirshfeld surface analysis indicates that the major contributions for the 1-O-methyl forbesione 1 packing are H⋯H (65.1%), H⋯O (23.2%) and H⋯C (9.7%) interactions.

Chiral resolution of a caged xanthone and evaluation across a broad spectrum of breast cancer subtypes

Racemic resolution of (+/−)-MAD28, a representative caged xanthone, was accomplished using (1S, 4R)-(−)-camphanic chloride as the chiral agent. Selective crystallization of the resulting diastereomers in acetonitrile produced, after hydrolysis, the pure enantiomers. Screening of racemic MAD28 and both enantiomers across a broad spectrum of breast cancer cell lines revealed that they: (a) are equipotent in each of the breast cancer subtypes examined; and (b) exhibit a higher degree of cytotoxicity against breast cancer cell lines of basal-like subtype and triple negative receptor status. The results support the notion that MAD28 and related caged xanthones are promising drug leads against chemoresistant and metastatic cancers.

A pair of new enantiomers of xanthones from the stems and leaves of Cratoxylum cochinchinense

BackgroundThe simple and caged xanthones from Clusiaceae showed significant antineoplastic activity. This study aims to identify structural diverse xanthones and search for novel antitumor natural products from this family plants.MethodsThe structures of new compounds 1a and 1b were elucidated mainly through comprehensive NMR and MS spectroscopic data, and their absolute configurations were determined by the comparison of the experimental and calculated electronic circular dichroism.ResultsA pair of new xanthone enantiomers, (+)- and (−)-cracochinxanthone A (1a and 1b), along with thirty known analogues (2–31), were isolated from extracts of the stems and leaves of C. cochinchinense. Preliminary biological assay of some isolates against HL-60, PC-3, and MDA-MB-231 cancer cell lines.ConclusionSome isolated xanthones exhibited high sensitivity against three human malignant cell lines and the structure–activity relationship study showed that the prenyl and geranyl units may play an important role in antitumor activity.