QSAR of aromatic substances: EGFR inhibitory activity of quinazoline analogues

The flip regression procedure that we used earlier for handling the xanthones system has been applied to phenylaminoquinazoline analogues. It is known that the substituents at the 6- and 7- positions of the polycyclic system have been identified as the most important structural features. The steric as well as the electrostatic interactions proved to be the most important for the inhibitory effect. In this contribution it is shown that the orientation of nodes in their occupied π orbitals, and also the energies of these orbitals explains a further large portion of the variance in their inhibitory activity.     

QSAR of aromatic substances: EGFR inhibitory activity of quinazoline analogues

The flip regression procedure that we used earlier for handling the xanthones system has been applied to phenylaminoquinazoline analogues. It is known that the substituents at the 6- and 7- positions of the polycyclic system have been identified as the most important structural features. The steric as well as the electrostatic interactions proved to be the most important for the inhibitory effect. In this contribution it is shown that the orientation of nodes in their occupied pi orbitals, and also the energies of these orbitals explains a further large portion of the variance in their inhibitory activity.     

Inhibitory effect of xanthones isolated from the pericarp of Garcinia mangostana L. on rat basophilic leukemia RBL-2H3 cell degranulation

Mangostin, Garcinia mangostana L. is used as a traditional medicine in southeast Asia for inflammatory and septic ailments. Hitherto we indicated the anticancer activity induced by xanthones such as alpha-, beta-, and gamma-mangostin which were major constituents of the pericarp of mangosteen fruits. In this study, we examined the effect of xanthones on cell degranulation in rat basophilic leukemia RBL-2H3 cells. Antigen (Ag)-mediated stimulation of high affinity IgE receptor (FcepsilonRI) activates intracellular signal transductions resulting in the release of biologically active mediators such as histamine. The release of histamine and other inflammatory mediators from mast cell or basophils is the primary event in several allergic responses. These xanthones suppressed the release of histamine from IgE-sensitized RBL-2H3 cells. In order to reveal the inhibitory mechanism of degranulation by xanthones, we examined the activation of intracellular signaling molecules such as Lyn, Syk, and PLCgammas. All the xanthones tested significantly suppressed the signaling involving Syk and PLCgammas. In Ag-mediated activation of FcepsilonRI on mast cells, three major subfamilies of mitogen-activated protein kinases were activated. The xanthones decreased the level of phospho-ERKs. Furthermore, the levels of phospho-ERKs were observed to be regulated by Syk/LAT/Ras/ERK pathway rather than PKC/Raf/ERK pathway, suggesting that the inhibitory mechanism of xanthones was mainly due to suppression of the Syk/PLCgammas/PKC pathway. Although intracellular free Ca(2+) concentration ([Ca(2+)](i)) was elevated by FcepsilonRI activation, it was found that alpha- or gamma-mangostin treatment was reduced the [Ca(2+)](i) elevation by suppressed Ca(2+) influx.     

Synthesis of new xanthone analogues and their biological activity test--cytotoxicity, topoisomerase II inhibition, and DNA cross-linking study

In this report, we prepared some 3-(2',3'-epoxypropoxy)xanthones and their epoxide ring opened halohydrin analogues, and evaluated their cytotoxicity and topoisomerase II inhibition activity using doxorubicin and etoposide as references, respectively. Another xanthone compound 9, 1,3-di(2',3'-epoxypropoxy)xanthone, was also synthesized and its DNA cross-linking property including other two biological activities investigated. The biological test results showed compound 9 possessed excellent cytotoxic and topoisomerase II inhibitory activity than other compounds tested. It also exhibited significant DNA cross-linking activities.     

Inhibition of protein kinase C by synthetic xanthone derivatives

The modulatory activity of two xanthones (3,4-dihydroxyxanthone and 1-formyl-4-hydroxy-3-methoxyxanthone) on isoforms alpha, betaI, delta, eta and zeta of protein kinase C (PKC) was evaluated using an in vivo yeast phenotypic assay. Both xanthones caused an effect compatible with PKC inhibition, similar to that elicited by known PKC inhibitors (chelerythrine and NPC 15437). PKC inhibition caused by xanthones was confirmed using an in vitro kinase assay. The yeast phenotypic assay revealed that xanthones present differences on their potency towards the distinct PKC isoforms tested. It is concluded that 3,4-dihydroxyxanthone and 1-formyl-4-hydroxy-3-methoxyxanthone may become useful PKC inhibitors and xanthone derivatives can be explored to develop new isoform-selective PKC inhibitors.     

Structure–activity relationships of diverse xanthones against multidrug resistant human tumor cells

Thirteen xanthones were isolated naturally from the stem of Securidaca inappendiculata Hassk, and structure-activity relationships (SARs) of these compounds were comparatively predicted for their cytotoxic activity against three human multidrug resistant (MDR) cell lines MCF-7/ADR, SMMC-7721/Taxol, and A549/Taxol cells. The results showed that the selected xanthones exhibited different potent cytotoxic activity against the growth of different human tumor cell lines, and most of the xanthones exhibited selective cytotoxicity against SMMC-7721/Taxol cells. Furthermore, some tested xanthones showed stronger cytotoxicity than Cisplatin, which has been used in clinical application extensively. The SARs analysis revealed that the cytotoxic activities of diverse xanthones were affected mostly by the number and position of methoxyl and hydroxyl groups. Xanthones with more free hydroxyl and methoxyl groups increased the cytotoxic activity significantly, especially for those with the presence of C-3 hydroxyl and C-4 methoxyl groups.     

Preparative isolation of closely-related xanthones from Gentianella amarella ssp. acuta by High-speed countercurrent chromatography

Introduction –  A methanolic extract from Gentianella amarella ssp. acuta was shown to contain several xanthones exhibiting acetylcholinesterase inhibitory activity. These xanthones were difficult to separate by conventional LC techniques, which prevented the isolation of pure compounds in sufficient amounts to perform in‐depth biological testing. Objective –  To develop a suitable preparative method for the separation of closely related xanthones. Methodology –  The methanolic extract was first partitioned with solvents of increasing polarity, in order to separate glycosides from xanthone aglycones. High‐speed countercurrent chromatography (HSCCC) methods were then optimised for the fractionation of both polar and non‐polar extracts. Results –  The use of HSCCC enabled the separation of xanthones which co‐eluted by HPLC. Ten closely related xanthones—three of which were isomeric—were successfully isolated by developing suitable solvent systems. All compounds were obtained in sufficient amounts to allow further biological assays (e.g. up to 250 mg), including even minor compounds that were not detectable by analytical HPLC. Conclusion –  The orthogonality of HSCCC with HPLC and the absence of solid‐phase supports enabled the detection, separation and preparative isolation of closely related compounds which were difficult to resolve by other techniques. Copyright © 2008 John Wiley & Sons, Ltd.     

<i>In Vitro</i> and <i>in Silico</i> Insights on the Biological Activities,Phenolic Compounds Composition of <i>Hypericum perforatum</i> L. Hairy Root Cultures

Three Hypericum perforatum hairy root lines (HR B, HR F and HR H) along with non-transformed roots were analyzed for phenolic compounds composition and in vitro enzyme inhibitory properties. In silico molecular modeling was performed to predict the interactions of the most representative phenolic compounds in HR clones with enzymes related to depression, neurodegeneration and diabetes. Chromatographic analyses revealed that HR clones represent an efficient source of quinic acid and hydroxybenzoic acids, epicatechin and procyanidin derivatives, quercetin and kaempferol glycosides, as well numerous xanthones. In vitro antidepressant activity of HR extracts through monoamine oxidase A (MAO-A) inhibition was attributed to the production of oxygenated and prenylated xanthones. The neuroprotective potential of HR extracts was related to the accumulation of quercetin 6-C-glucoside, epicatechin, procyanidins and γ-mangostin isomers as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Vanillic acid and prenylated xanthones in HR clones as promising inhibitors of tyrosinase additionally contributed to the neuroprotective activity. Five preeminent xanthones in HR (γ-mangostin, mangiferin, garcinone C, garcinone E and 1,3,7-trihydroxy-6-metoxy-8-prenyl xanthone) along with the flavonol quercetin 6-C-glucoside effectively inhibited α-amylase and α-glucosidase indicating the antidiabetic properties of HR extracts. Transgenic roots of H. perforatum can be exploited for the preparation of novel phytoproducts with multi-biological activities.     

Xanthones and Cancer: from Natural Sources to Mechanisms of Action

Xanthones are a class of heterocyclic natural products that have been widely studied for their pharmacological potential. In fact, they have been serving as scaffolds for the design of derivatives focusing on drug development. One of the main study targets of xanthones is their anticancer activity. Several compounds belonging to this class have already demonstrated cytotoxic and antitumor effects, making it a promising group for further exploration. This review therefore focuses on recently published studies, emphasizing their natural and synthetic sources and describing the main mechanisms of action responsible for the anticancer effect of promising xanthones.     

Antioxidant and cytotoxic activities of xanthones from Cudrania tricuspidata

The new catecholic xanthone, 1,3,7-trihydroxy-4-(1,1-dimethyl-2-propenyl)-5,6-(2,2-dimethylchromeno)-xanthone (1), was isolated from the root bark of Cudrania tricuspidata together with seven known xanthones. The structures were fully characterized by analysis of physical and spectral (UV, IR, mass, and NMR) data. Relationships between the structural characteristics of xanthones and their antioxidant activities (DPPH, superoxide, and hydroxyl radical) were studied. Among the range of catecholic xanthones, 6,7-dihydroxyl xanthones (3–8) exhibited a strong scavenging effect on the DPPH radical. When one of the catecholic hydroxyl groups was protected as in compounds 1 and 2, DPPH radical scavenging activity was markedly decreased (IC₅₀ > 200 μM). DPPH activities were consistent with electrochemical response by cyclic voltammetry. Interestingly, compounds (1, 2) which had the weak activities on DPPH, exhibited both potent superoxide and hydroxyl radical scavenging activities. The strong activity on the hydroxyl radical of compounds (1, 2) could be rationalized by their chelating effect with iron (Fe²⁺) due to a redshift of its complex. The catecholic xanthones (3–8), being able to convert quinone methide intermediate, showed potent cytotoxicities against human cancer cell lines (HT-29, HL-60, SK-OV3, AGS, and A549). In particular, compounds 3, 6, and 7 had strong cytotoxic activities against AGS (LD₅₀ < 5 μM). DNA fragmentation patterns induced by catecholic xanthones revealed that tumor cell death was due to apoptosis.     

Anti-inflammatory activity of benzophenone and xanthone derivatives isolated from Garcinia (Clusiaceae) species

Species of the genus Garcinia have been the source of many benzophenone and xanthone derivatives. Recent data regarding potent biological properties of natural compounds in Garcinia species led us to investigate the in vitro anti-inflammatory effect of three known xanthones, lichexanthone (1), 1,3,6,7-tetrahydroxyxanthone (2), 1,3,5,6-tetrahydroxyxanthone (3), two new xanthones 1-hydroxy-3,6,7-tri-O,O,O-triprenylxanthone (4), 1,6-dihydroxy-3,7-di-O,O-diprenylxanthone (5) and two benzophenones isoxanthochymol (6), guttiferone E (7), isolated from Garcinia nobilis and Garcinia punctata. The Griess assay was used for the measurement of nitric oxide (NO) production in RAW264.7 macrophages and the ferrous oxidation-xylenol orange assay was used to determine the 15-lipoxygenase (15-LOX) inhibitory activity. All the compounds had inhibitory effect on 15-LOX activity to different extents. Compound (7) had the highest anti-LOX activity with an IC₅₀ value of 43.05 μg/mL. At the highest studied concentration (25 μg/mL), compound (4) had the most potent inhibitory activity against NO release with a% of inhibition of 95.42% and less cytotoxic effect on RAW264.7 cells (% of cell viability of 81.40).The results presented here suggest that 1,3,5,6-tetrahydroxyxanthone (3) and guttiferone E (7) are promising inhibitors of NO production and 15-LOX activity. Further studies should be considered in order to elucidate the mechanism by which these compounds exert their inhibitory activities.     

Root cultures of <Emphasis Type="Italic">Hypericum perforatum</Emphasis> subsp. <Emphasis Type="Italic">angustifolium</Emphasis> elicited with chitosan and production of xanthone-rich extracts with antifungal activity

Hypericum perforatum is a well-known medicinal plant which contains a wide variety of metabolites, including xanthones, which have a wide range of biological properties, including antifungal activity. In the present study, we evaluated the capability of roots regenerated from calli of H. perforatum subsp. angustifolium to produce xanthones. Root biomass was positively correlated with the indole-3-butyric acid concentration, whereas a concentration of 1 mg l⁻¹ was the most suitable for the development of roots. High auxin concentrations also inhibited xanthone accumulation. Xanthones were produced in large amounts, with a very stable trend throughout the culture period. When the roots were treated with chitosan, the xanthone content dramatically increased, peaking after 7 days. Chitosan also induced a release of these metabolites into the culture. The maximum accumulation (14.26 ± 0.62 mg g⁻¹ dry weight [DW]) and release (2.64 ± 0.13 mg g⁻¹ DW) of xanthones were recorded 7 days after treatment. The most represented xanthones were isolated, purified, and spectroscopically characterized. Antifungal activity of the total root extracts was tested against a broad panel of human fungal pathogen strains (30 Candida species, 12 Cryptococcus neoformans, and 16 dermatophytes); this activity significantly increased when using chitosan. Extracts obtained after 7 days of chitosan treatment showed high antifungal activity (mean minimum inhibitory concentration of 83.4, 39.1, and 114 μg ml⁻¹ against Candida spp., C. neoformans, and dermatophytes, respectively). Our results suggest that root cultures can be considered as a potential tool for large-scale production of extracts with stable quantities of xanthones.     

Synthesis and in vivo modulatory activity of protein kinase C of xanthone derivatives

The modulatory activity of a series of 20 simple xanthones on isoforms alpha, betaI, delta, eta and zeta of protein kinase C (PKC) was evaluated using an in vivo yeast phenotypic assay. Hydroxy and/or methoxyxanthones were synthesised. The majority of these compounds caused an effect compatible with activation of PKC and some showed to be more effective than the standard PKC activator (PMA or arachidonic acid). The xanthones tested differ in their efficacy and potency towards individual PKC isoforms and some showed higher selectivities for PKC-delta, -eta or -zeta, suggesting that xanthone derivatives can become valuable research tools to elucidate the physiological roles of these isoforms.     

Antimicrobial activity of isoprenoid-substituted xanthones from Cudrania cochinchinensis against vancomycin-resistant enterococci.

Ten xanthones with one or two isoprenoid groups and a prenylated benzophenone isolated from roots of Cudrania cochinchinensis (Moraceae) were tested for their antimicrobial activities against vancomycin-resistant enterococci (VRE). Among these compounds, gerontoxanthone H exhibited considerable antibacterial activity against five VRE strains (VanA, VanB and VanC) (MICs = 1.56 microg/ml). Four xanthones, 1,3,7-trihydroxy-2-prenylxanthone, gerontoxanthone I, alvaxanthone and isoalvaxanthone, showed weaker antibacterial activity against these VREs (MICs = 3.13-6.25 microg/ml). .     

Definition of an electronic profile of compounds with inhibitory activity against hematin aggregation in malaria parasite

Malaria is one of the most important parasitic diseases, affecting almost half of the world and posing a threat to the other half. Xanthone derivatives can behave as antimalarial drugs in the same mechanistic way as chloroquine and other related quinolines. This action is due to the inhibition of the detoxification pathway of the parasite, responsible for the production of hemozoin. We report a study of the electronic properties of the xanthonic and quinolinic compounds based on DFT calculations, in order to determine a pattern that could be applied to the development of new potentially active antimalarial molecules. As a result, a new interpretation of structure-activity relationship of the quinoline antimalarial drugs, and of the active hydroxylated xanthones is proposed here. We conclude that electronic features rather than steric factors control primarily the inhibitory activity of the studied compounds against hematin aggregation, concurring to a potential antimalarial activity.     

Vasodilatory actions of xanthones isolated from a Tibetan herb,Halenia elliptica

In this study, six major xanthones, isolated and identified from Halenia elliptica were investigated for their vasodilatory actions in isolated rat coronary artery. The xanthones, including 1-hydroxy-2,3,5-trimethoxy-xanthone (HM-1), 1-hydroxy-2,3,4,7-tetramethoxy-xanthone (HM-2), 1-hydroxy-2,3,4,5-tetramethoxy-xanthone (HM-3), 1,7-dihydroxy–2,3,4,5-tetramethoxy-xanthone (HM-4), 1,5-dihydroxy-2,3-dimethoxy-xanthone (HM-5) and 1,7-dihydroxy-2,3-dimethoxy-xanthone (HM-7) caused vasodilation in the coronary artery pre-contracted with 1 μM 5-hydroxytryptamine (5-HT), with EC₅₀ values ranging from 1.4±0.1 μM (HM-1) to 6.6±1.4 μM (HM-2). The EC₅₀ values of the other xanthones were between those of HM-1 and HM-2. Removal of endothelium of the coronary artery led to decreases in the vasorelaxant effects of HM-1, HM-7 but not HM-2, HM-3, HM-4 and HM-5. Our results showed that xanthones isolated from Halenia elliptica are vasoactive substances which exhibit either endothelium-dependent or endothelium-independent mechanisms in rat coronary artery. The potency and mechanism(s) of the vasorelaxant effects of these xanthones may be relevant to the structure–activity differences in the level and the position of the substituent groups with the primary xanthone structure.     

Vasodilatory actions of xanthones isolated from a Tibetan herb,Halenia elliptica

In this study, six major xanthones, isolated and identified from Halenia elliptica were investigated for their vasodilatory actions in isolated rat coronary artery. The xanthones, including 1-hydroxy-2,3,5-trimethoxy-xanthone (HM-1), 1-hydroxy-2,3,4,7-tetramethoxy-xanthone (HM-2), 1-hydroxy-2,3,4,5-tetramethoxy-xanthone (HM-3), 1,7-dihydroxy–2,3,4,5-tetramethoxy-xanthone (HM-4), 1,5-dihydroxy-2,3-dimethoxy-xanthone (HM-5) and 1,7-dihydroxy-2,3-dimethoxy-xanthone (HM-7) caused vasodilation in the coronary artery pre-contracted with 1 μM 5-hydroxytryptamine (5-HT), with EC₅₀ values ranging from 1.4±0.1 μM (HM-1) to 6.6±1.4 μM (HM-2). The EC₅₀ values of the other xanthones were between those of HM-1 and HM-2. Removal of endothelium of the coronary artery led to decreases in the vasorelaxant effects of HM-1, HM-7 but not HM-2, HM-3, HM-4 and HM-5. Our results showed that xanthones isolated from Halenia elliptica are vasoactive substances which exhibit either endothelium-dependent or endothelium-independent mechanisms in rat coronary artery. The potency and mechanism(s) of the vasorelaxant effects of these xanthones may be relevant to the structure–activity differences in the level and the position of the substituent groups with the primary xanthone structure.     

Xanthones protects lead-induced chronic kidney disease (CKD) via activating Nrf-2 and modulating NF-kB,MAPK pathway

Xanthones from a tropical fruit of Garcinia mangostana L. is known to possess a wide spectrum of pharmacologic properties, including antioxidant, anti-bacterial, anti-inflammatory, and antidiabetic activities. The current study aimed to assess the possible protective effects of xanthones against lead acetate (PbAc)-induced chronic kidney disease (CKD). To accomplish, in vitro antioxidant assays of xanthones, in vivo oxidative stress parameters, histopathology, inflammatory parameters were evaluated using PbAc-induced IRC male mice. The study was supported by in silico molecular docking of respective organ receptor protein-ligand interaction. Results revealed that xanthones potentially scavenged the DPPH, superoxide, hydroxyl, and nitric oxide radicals. Oxidative stress, kidney dysfunction, inflammatory markers, and kidney apoptosis increased by PbAc were attenuated with the co-treatment of xanthones. The treatment remarkably improved the tissue architecture. Of note, in silico prediction of activity study showed that protective role of xanthones could be due to its efficacy to activate the Nrf-2, regulate the intracellular [Ca²⁺], as well as downregulate the NF-kB, MAPK pathway. In a nutshell, xanthones could be a potential candidate for the management of PbAc-induced kidney damage.