Xanthone Ring Research Articles

Molecular docking studies and in-vitro cholinesterase inhibitory activities of chemical constituents of Calophyllum gracilentum

Calophyllum species are well known due to their abundance of potentially beneficial phytochemicals, such as xanthones, coumarins, and others. However, Calophyllum gracilentum is an understudied specie with very limited information. Medicinal plants have been proven to have therapeutic potential in managing neurological disorders associated with acetylcholinesterase (AChE) dysregulation. Still, there has been little investigation on Calophyllum plants for this purpose. Herein, we report on the isolation of a new oxygenated xanthone 5,10-dihydroxy-9-methoxy-2,2-dimethyl-12-(3-methylbut-2-enyl) pyrano[3,2-b] xanthen-6(2 H)-one (1) and eleven known xanthones (2–12), three chromanone acids (13–15), and phytosterols (16–18), respectively from the stem bark of the Calophyllum gracilentum. The evaluation of AChE inhibitory activity showed that all the extracts and xanthones (2, 5, 6, 8, 9, 12) tested have potential AChE inhibitory activity. Compounds (5) and (12) are prospective AChE inhibitors with IC50 values of 1.8 ± 0.0001 and 4.0 ± 0.0002 µmol/L. The molecular docking analysis demonstrated compound (5) and compound (12) bind well to the active site which is the anionic site containing Trp 84 and Asp 72 in the of Torpedo californica acetylcholinesterase (TcAChE) through π-π stacking, hydrogen bonding, and π-donor hydrogen bond from the xanthone ring, besides π-alkyl and π-σ interactions from the substituent group with the binding energy of −11.1 kcal/mol for compound (5) and binding energy of −10.4 kcal/mol for compound (12).

Hyperthermia Intensifies α-Mangostin and Synthetic Xanthones' Antimalignancy Properties.

In order to improve naturally occurring xanthones' anticancer properties, chemical synthesis is proposed. In this study, from eight novel xanthone derivatives coupled to morpholine or aminoalkyl morpholine, only the two most active ones were chosen. For additional enhancement of the anticancer activity of our tested compounds, we combined chemotherapy with hyperthermia in the range of 39-41 °C, from which the mild conditions of 39 °C were the most influencing. This approach had a profound impact on the anticancer properties of the tested compounds. TOV-21G and SC-OV-3 ovarian cell line motility and metastasis behavior were tested in native and hyperthermia conditions, indicating decreased wound healing properties and clonogenic activity. Similarly, the expression of genes involved in metastasis was hampered. The expression of heat shock proteins involved in cancer progression (Hsc70, HSP90A, and HSP90B) was significantly influenced by xanthone derivatives. Chemotherapy in mild hyperthermia conditions had also an impact on decreasing mitochondria potential, visualized with JC-1. Synthetic xanthone ring modifications may increase the anticancer activity of the obtained substances. Additional improvement of their activity can be achieved by applying mild hyperthermia conditions. Further development of a combined anticancer therapy approach may result in increasing currently known chemotherapeutics, resulting in a greater recovery rate and diminishment of the cytotoxicity of drugs.

Synthesis of 1-hydroxy-3-O-substituted xanthone derivatives and their structure-activity relationship on acetylcholinesterase inhibitory effect

This study focused on the synthesis of 1,3-dihydroxyxanthone (1) and its new derivatives with alkyl (2a–2f), alkenyl (2 g–2k), alkynyl (2 l–2n), and alkylated phenyl (2o–2r) groups at C3 position. The structures of these compounds were confirmed by MS, NMR, and FTIR spectroscopic data. All the substituted xanthones (2a–2r) showed significantly stronger acetylcholinesterase (AChE) inhibitory activities than 1. Compounds 2g and 2j exhibited the strongest activities with the IC50 values of 20.8 and 21.5 μM and their enzyme kinetic analyses indicated a mixed-mode inhibition. Molecular docking study revealed that 2g binds favourably to the active site of AChE via π–π stacking and hydrogen bonding from the xanthone ring, in addition to π-alkyl interaction from the substituent group. These xanthone derivatives are potential lead compounds to be further developed into Alzheimer’s disease drugs.

Xanthone Biosynthetic Pathway in Plants: A Review.

Xanthones are secondary metabolites rich in structural diversity and possess a broad array of pharmacological properties, such as antitumor, antidiabetic, and anti-microbes. These aromatic compounds are found in higher plants, such as Clusiaceae, Hypericaceae, and Gentianaceae, yet their biosynthetic pathways have not been comprehensively updated especially within the last decade (up to 2021). In this review, plant xanthone biosynthesis is detailed to illuminate their intricacies and differences between species. The pathway initially involves the shikimate pathway, either through L-phenylalanine-dependent or -independent pathway, that later forms an intermediate benzophenone, 2,3′,4,6-tetrahydoxybenzophenone. This is followed by a regioselective intramolecular mediated oxidative coupling to form xanthone ring compounds, 1,3,5-trihydroxyxanthone (1,3,5-THX) or 1,3,7-THX, the core precursors for xanthones in most plants. Recent evidence has shed some lights onto the enzymes and reactions involved in this xanthone pathway. In particular, several biosynthetic enzymes have been characterized at both biochemical and molecular levels from various organisms including Hypericum spp., Centaurium erythraea and Garcinia mangostana. Proposed pathways for a plethora of other downstream xanthone derivatives including swertianolin and gambogic acid (derived from 1,3,5-THX) as well as gentisin, hyperixanthone A, α-mangostin, and mangiferin (derived from 1,3,7-THX) have also been thoroughly covered. This review reports one of the most complete xanthone pathways in plants. In the future, the information collected here will be a valuable resource for a more directed molecular works in xanthone-producing plants as well as in synthetic biology application.

An asymmetric performance between mangiferin and isomangiferin as antioxidants

Abstract The electronic performance between mangiferin and isomangiferin as antioxidants was achieved using electron and hydrogen atom transfer mechanisms at DFT/B3LYP/6-31+G(d,p) level. According to theoretical properties of these molecules a structural and electronic symmetry among 3-hydroxyl of xanthone, 2’-hydroxyl of sugar, and ether moiety of sugar were stablished. The sugar moiety changes on 2 and 4 positions showed that isomangiferin is more potent than mangiferin by electron transfer and mangiferin by hydrogen transfer. Hydrogen bonds between sugar and resorcinol rings can be involved to their electronic behavior and favored conformations of low energies. Sugar moiety in both compounds is responsible for the antioxidant capacity increase in xanthone ring.

Sugar moiety has a synergistic effect on hydroxylated xanthone for better antioxidant activity of mangiferin

The structure–antioxidant relationship of mangiferin was elucidated by means of quantum chemistry calculations. The density functional theory level of theory was used for antioxidant pharmacophore selection. According to the obtained geometry by using the DFT/B3LYP/6-31+G(d,p) values, HOMO, ionization potential, bond dissociation energy, stabilization energy, and spin density distribution, the catechol moiety is more important for the antioxidant capacity than the resorcinol moiety. However, the sugar is a strong electron-withdrawing group due to its hydrogen bond formation with the resorcinol moiety of xanthone ring. The hydrogen transfer is more important for the antioxidant activity than the electron transfer. The hydrogen abstractions in the ortho positions are more favored than the meta positions. Thus, our results show a synergistic effect between xanthone and sugar rings.

A Multifunctional Monooxygenase XanO4 Catalyzes Xanthone Formation in Xantholipin Biosynthesis via a Cryptic Demethoxylation

Xantholipin and several related polycyclic xanthone antibiotics feature a unique xanthone ring nucleus within a highly oxygenated, angular, fused hexacyclic system. In this study, we demonstrated that a flavin-dependent monooxygenase (FMO) XanO4 catalyzes the oxidative transformation of an anthraquinone to a xanthone system during the biosynthesis of xantholipin. Invitro isotopic labeling experiments showed that the reaction involves sequential insertion of two oxygen atoms, accompanied by an unexpected cryptic demethoxylation reaction. Moreover, characterizations of homologous FMOs of XanO4 suggested the generality of the XanO4-like-mediated reaction for the assembly of a xanthone ring in the biosynthesis of polycyclic xanthone antibiotics. These findings not only expand the repertoire of FMO activities but also reveal a novel mechanism for xanthone ring formation.

Cytotoxic Activity and DNA-Binding Properties of Isoeuxanthone Derivatives

In this study, the interactions of different groups substituted isoeuxanthone derivatives with calf thymus DNA (ct DNA) were investigated by spectrophotometric methods and viscosity measurements. Results indicated that the xanthone derivatives could intercalate into the DNA base pairs by the plane of xanthone ring and the various substituents may influence the binding affinity with DNA according to the calculated quenching constant values. Furthermore, two tumor cell lines including the human cervical cancer cell line (HeLa) and human hepatocellular liver carcinoma cell line (HepG2) were used to evaluate the cytotoxic activities of xanthone derivatives by acid phosphatase assay. Analyses showed that the oxiranylmethoxy substituted xanthone exhibited more effective cytotoxic activity against the cancer cells than the other substituted xanthones. The effects on the inhibition of tumor cells in vitro agreed with the studies of DNA-binding.

Antitumor Activity and DNA-Binding Investigations of Isoeuxanthone and Its Piperidinyl Derivative

The binding mode and affinity of isoeuxanthone (1,6-dihydroxyxanthone) (1) and its piperidinyl derivative (1-hydroxy-6-(2-(1-piperidinyl)ethoxy)xanthone) (2) with calf thymus DNA were studied using absorption spectroscopy, fluorescence spectroscopy, circular dichroism (CD) spectroscopy and viscosity measurements. Results indicate that the two xanthones can intercalate into the DNA base pairs by the plane of xanthone ring and the binding affinity of the piperidinylethoxy substituted xanthone 2 is stronger than 1. In addition, the cytotoxic effects of both compounds were evaluated with the human cervical cancer cell line (HeLa) and human hepatocellular liver carcinoma cell line (HepG2) using acid phosphatase assay. Analyses show that the piperidinylethoxy substituted xanthone exhibits more effective cytotoxic activity than isoeuxanthone against the two cancer cells. The effects on the inhibition of tumor cells in vitro agree with the studies of DNA-binding.

3-O-Methyl-1-isomangostin

In the title xanthone derivative [systematic name: 9-hy­droxy-5,10-dimeth­oxy-2,2-dimethyl-11-(3-methyl­but-2-en-1-yl)-2,3,4,12-tetra­hydro-1,7-dioxatetra­phen-12-one], C25H28O6, the xanthone ring system is roughly planar, with an r.m.s. deviation of 0.1038 (1) Å. The chromane ring is in a half-chair conformation and the 3-methyl­but-2-enyl substituent is axially attached with an (+)-anti­clinal conformation. Two weak intra­molecular C—H⋯O inter­actions generate two S(6) ring motifs. In the crystal, mol­ecules are linked into ribbons along the c axis by O—H⋯O and weak C—H⋯O hydrogen bonds. A π–π inter­action, with a centroid–centroid distance of 3.5413 (8) Å, is also observed.

Caloxanthone C: a pyranoxanthone from the stem bark ofCalophyllum soulattri

The title compound [systematic name: 5,10-di­hy­droxy-2,2-di­methyl-12-(2-methyl­but-3-en-2-yl)­pyrano[3,2-b]xanthen-6(2H)-one], C23H22O5, isolated from the stem bark of Calophyllum soulattri, consists of four six-membered rings and a 2-methyl­but-3-en-2-yl side chain. The tricyclic xanthone ring system is almost planar [maximum deviation = 0.093 (2) Å], whereas the pyran­oid ring is in a distorted boat conformation. The 2-methyl­but-3-en-2-yl side chain is in a synperiplanar conformation. There are two intra­molecular O—H⋯O hydrogen bonds. In the crystal, mol­ecules are linked by C—H⋯O inter­actions, forming a zigzag chain propagating in [010].

12-Acetyl-6-hy-droxy-3,3,9,9-tetra-methyl-furo[3,4-b]pyrano[3,2-h]xanthene-7,11(3H,9H)-dione.

The title compound, Artonol B, C24H20O7, isolated from the stem bark of Artocarpus kemando, consists of four six-membered rings and one five-membered ring. The tricyclic xanthone ring system is almost planar [maximum deviation 0.115 (5) Å], whereas the pyran­oid ring is in a distorted boat conformation·The furan ring is almost coplanar with the fused aromatic ring, making a dihedral angle of 3.76 (9)°. The phenol ring serves as a intra­molecular hydrogen-bond donor to the adjacent carbonyl group and also acts as an inter­molecular hydrogen-bond acceptor for the methyl groups of adjacent mol­ecules, forming a three-dimensional network in the crystal.

Fluorescence Quenching by Photoinduced Electron Transfer in the Zn2+ Sensor Zinpyr-1: A Computational Investigation

We report a detailed study of luminescence switching in the fluorescent zinc sensor Zinpyr-1 by density functional methods. A two-pronged approach employing both time-dependent density functional theory (TDDFT) and constrained density functional theory (CDFT) is used to characterize low-lying electronically excited states of the sensor. The calculations indicate that fluorescence activation in the sensor is governed by a photoinduced electron transfer mechanism in which the energy level ordering of the excited states is altered by binding Zn(2+). While the sensor is capable of binding two Zn(2+) cations, a single Zn(2+) ion appears to be sufficient to activate moderate fluorescence in aqueous solution at physiological pH. We show that it is reasonable to consider the tertiary amine as the effective electron donor in this system, although the pyridyl nitrogens each contribute some density to the xanthone ring. The calculations illustrate an important design principle: because protonation equilibria at receptor sites can play a determining role in the sensor's fluorescence response, receptor sites with a pK(a) near the pH of the sample are to be disfavored if a sensor governed by a simple PET fluorescence quenching model is desired.

Cytotoxic Activity and DNA-binding Properties of Xanthone Derivatives

In this study, the interactions of different groups substituted xanthone derivatives with calf thymus DNA (ct DNA) have been investigated by spectrophotometric methods and viscosity measurements. Results indicate that xanthone derivatives can intercalate into the DNA base pairs by the plane of xanthone ring and the various substituents may influence the binding affinity with DNA according to the calculated quenching constant values and the melting temperature of DNA. Furthermore, three tumor cell lines including esophagus squamous cancer cell line (ECA109), stomach cancer cell line (SGC7901) and lung cancer cell line (GLC-82) have been used to evaluate the cytotoxic activities of xanthone derivatives by MTT (microculture tetrazolium) method. Analysis show that the oxiranylmethoxy or piperidinylethoxy substituted xanthones exhibit more effective cytotoxic activity against three cancer cells than the other substituted xanthones. The effects on the inhibition of tumor cells in vitro agree with the studies of DNA-binding.

7-Acetoxycochinchinone I

The title compound {systematic name: 12-[(2E)-3,7-dimethyl-2,6-octa­dien­yl]-5,8-dihydr­oxy-2,2-dimethyl-2H,6H-pyrano[3,2-b]xanthen-6-one}, C30H32O6, has four fused rings (A/B/C/D) and the xanthone ring system (A/B/C) is essentially planar, with dihedral angles of 1.85 (13) and 2.47 (13)°, respectively, between rings A and B, and between rings B and C. The chromene ring D is in a sofa form. The geranyl side chain is axially attached to ring C with an (−)-synclinal conformation. The 3-methyl-2-butenyl terminal of the geranyl side chain is disordered with the site-occupancy ratio of 0.513 (5):0.487 (5). The acet­oxy group is attached axially to ring A with an (+)-synclinal conformation. An intra­molecular O—H⋯O hydrogen bond involving the carbonyl and hydroxyl groups generates an S(6) ring motif. In the crystal, weak C—H⋯O and C—H⋯π inter­actions, and π–π inter­actions with centroid–centroid distances of 3.6562 (16) and 3.6565 (16) Å are observed.

Synthesis, Crystal Structure, DNA-binding Properties and Cytotoxic Activity of the Copper (II) Complex Involving Xanthone

1, 8-(3, 6, 9-Trioxaundecane-1, 11-diyldioxy)xanthone (L), and its new Cu (II) complex [Cu.L.(CH3CN)2](ClO4)2 have been synthesized and characterized by 1H NMR, electrospray mass spectra (ESI-MS), elemental analyses, infrared spectra (IR) and X-ray single crystal diffraction. The crystal structure of complex shows that Cu (II) ion is encapsulated within the macrocycle of L. The geometry around copper is a distorted square bipyramid with two acetonitrile molecules at axial position, and four macrocyclic oxygens including the carbonyl oxygen on the equatorial positions. The interaction of Cu (II) complex with calf thymus DNA (ct DNA) has been investigated by spectrophotometric titrations, ethidium bromide (EB) displacement experiments, circular dichroism (CD) spectra and viscosity measurements. Results indicate that Cu (II) complex can intercalate into the DNA base pairs by the plane of xanthone ring. Furthermore, the Cu (II) complex was tested against tumor cell lines including ECA109, SGC7901 and GLC-82 by MTT (microculture tetrazolium) method. The studies of DNA-binding agree with the effects on the inhibition of tumor cells in vitro.

Structure–Activity Relationships and Binding Mode in the Human Acetylcholinesterase Active Site of Pseudo‐Irreversible Inhibitors Related to Xanthostigmine

Structure-activity relationship studies on acetylcholinesterase (AChE) inhibitors were extended to newly synthesized compounds derived from the lead compound xantostigmine (1). The xanthone ring of compound 1 was replaced with several different scaffolds based on the benzopyran skeleton, linked to the tertiary amino nitrogen through an heptyloxy chain. These modifications resulted in 19 new compounds, most of them showing activity in the nanomolar-subnanomolar range. Docking and molecular dynamics simulations were carried out to both define a new computational protocol for the simulation of pseudo-irreversibile AChE covalent inhibitors, and to acquire a better understanding of the structure-activity relationships of the present series of compounds. The results of this computational work prompted us to to evaluate the ability of compounds 5 and 13 to inhibit acetylcholinesterase-induced Abeta aggregation.

Isolation and structure elucidation of parnafungins C and D, isoxazolidinone-containing antifungal natural products

Parnafungins, natural products containing an isoxazolidinone ring, have been isolated from Fusarium larvarum and have been shown to be potent inhibitors of the fungal polyadenosine polymerase. The extraction and analysis of fermentation broths of taxonomically related organisms identified as closely related Fusarium spp. produce not only parnafungin A and B, but also significant quantities of two related components. These members of the paranfungin family of natural products have been isolated and the structure of each has been elucidated. While structurally analogous to parnafungin A, parnafungin C is further elaborated by methylation of a phenolic hydroxyl group, and parnafungin D has both the methyl phenol ether as well as an epoxide in the xanthone ring system. Parnafungin C and D have potent, broad spectrum antifungal activity and also have been shown to target fungal mRNA cleavage and polyadenylation.

Isolation and Structure Elucidation of Parnafungins, Antifungal Natural Products that Inhibit mRNA Polyadenylation

The Candida albicans Fitness Test, a whole-cell screening platform, was used to profile crude fermentation extracts for novel antifungal natural products with interesting mechanisms of action. An extract with intrinsic antifungal activity from the fungus Fusarium larvarum displayed a Fitness Test profile that strongly implicated mRNA processing as the molecular target responsible for inhibition of fungal growth. Isolation of the active components from this sample identified a novel class of isoxazolidinone-containing natural products, which we have named parnafungins. These natural products were isolated as an interconverting mixture of four structural- and stereoisomers. The isomerization of the parnafungins was due to a retro-Michael ring-opening and subsequent reformation of a xanthone ring system. This interconversion was blocked by methylation of an enol moiety. Structure elucidation of purified parnafungin derivatives was accomplished by X-ray crystallography and NMR analysis. The biochemical target of these natural products has been identified as the fungal polyadenosine polymerase. Parnafungins demonstrated broad spectrum antifungal activity with no observed activity against gram-positive or gram-negative bacteria. The intact isoxazolidinone ring was required for antifungal activity. In addition, the natural products were efficacious in a mouse model of disseminated candidiasis.

4,8-Dihydroxy-2,3-dimethoxy-1-(3-methylbut-2-enyl)-9H-xanthen-9-one

The title xanthone compound, C20H20O6, was isolated from the roots of Cratoxylum formosum ssp. pruniflorum. The xanthone ring system is essentially planar. The 3-methyl­but-2-enyl substituent plane is not coplanar with the attached benzene ring, the dihedral angle being 62.59 (12) A. The two meth­oxy groups are twisted away from the mean plane of the attached benzene ring. The two hydr­oxy groups are coplanar with the attached benzene rings and contribute to O—H⋯O intra­molecular hydrogen bonds which generate S(5) and S(6) ring motifs. In the crystal structure, inter­molecular O—H⋯O hydrogen bonds and weak C—H⋯O inter­molecular inter­actions connect the mol­ecules into infinite one-dimensional chains along the [201] direction. The crystal is further stabilized by C—H⋯π inter­actions.