Xanthones Isolated from Cratoxylum cochinchinensis Reduced Oxidative Stress in Periodontal Ligament Stem Cells.

Xanthone compounds from Cratoxylum cochinchinensis (C. cochinchinensis) have demonstrated antioxidant effects and potency in treating many inflammatory diseases. However, the efficiency of the three xanthone extracts isolated from the young fruit of this plant, i.e., two geranyloxy xanthones (F6, F8) and one 1,3,7-hydroxy xanthone (F137), as antioxidants and therapeutics for periodontal disease has not been evaluated. The aim of this study was to investigate the antioxidant effects of three xanthones isolated from C. cochinchinensis on periodontal ligament stem cells (PDLSCs) and their osteogenic differentiation. The antioxidant activity of the aqueous extracts was determined using a DPPH assay, and their cytotoxicity was evaluated using an MTT assay. H2O2 was used to induce intracellular stress, and the scavenging effect of the isolated compounds against reactive oxygen species (ROS) was analyzed with a fluorescence assay. The expression of nuclear factor-erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) was evaluated, and the effects of the three compounds on PDLSCs osteogenic differentiation were investigated. The isolated compounds reduced both extracellular and intracellular ROS in a dose-dependent manner and induced the expression of Nrf2 and HO-1 in PDLSCs. Under redox conditions, these compounds potentiated PDLSCs osteogenic differentiation. Our study demonstrated that the hydroxy xanthones from C. cochinchinensis had antioxidant effects on the Nrf2/HO-1 pathway and might be effective therapeutic substrates for damage prevention and the regeneration of damaged periodontal tissues in periodontitis patients.

Modified tetra-oxygenated xanthones analogues as anti-MRSA and P. aeruginosa agent and their synergism with vancomycin.

Five isolated xanthones from the C. cochinchinense and G. mangostana were evaluated and tested for antibacterial activities. Isolated 4 and 5 exhibited potent anti-MRSA and P. aeruginosa activity, but showed poor pharmacokinetic properties via ADMET prediction. It led us to improve pharmacokinetic properties of 4 and 5 by partially modifying them in acidic condition yielding fourteen analogues. It was found that analogues 4b, 4d and 5b possessed proper pharmacokinetic properties, while only 4b exhibited the best anti-MRSA and P. aeruginosa activity. The SEM results indicated that 4b may interact with or damage the cell wall of MRSA and P. aeruginosa. Moreover, a combination of 4b and vancomycin exhibits synergistic effect against both MRSA and P. aeruginosa at MIC value of 4.98 (MIC = 18.75 µg/mL for 4b) and 9.52 µg/mL (MIC = 75 µg/mL for 4b), respectively.

The Intestinal Efflux Transporter Inhibition Activity of Xanthones from Mangosteen Pericarp: An In Silico, In Vitro and Ex Vivo Approach.

The capacity of α-mangostin (α-MG) and ß-mangostin (ß-MG) from mangosteen pericarp on P-glycoprotein (Pgp) in silico, in vitro, and ex vivo was investigated in this study. Screening with the ADMET Predictor™ program predicted the two compounds to be both a Pgp inhibitor and Pgp substrate. The compounds tended to interact with Pgp and inhibit Pgp ATPase activity. Additionally, bidirectional transport on Caco-2 cell monolayers demonstrated a significantly lower efflux ratio than that of the control (α-(44.68) and ß-(46.08) MG versus the control (66.26); p < 0.05) indicating an inhibitory effect on Pgp activity. Test compounds additionally revealed a downregulation of MDR1 mRNA expression. Moreover, an ex vivo absorptive transport in everted mouse ileum confirmed the previous results that α-MG had a Pgp affinity inhibitor, leading to an increase in absorption of the Pgp substrate in the serosal side. In conclusion, α- and ß-MG have the capability to inhibit Pgp and they also alter Pgp expression, which makes them possible candidates for reducing multidrug resistance. Additionally, they influence the bioavailability and transport of Pgp substrate drugs.

Caged-xanthone from Cratoxylum formosum ssp. pruniflorum inhibits malignant cancer phenotypes in multidrug-resistant human A549 lung cancer cells through down-regulation of NF-κB.

Our recent study reported that multidrug-resistant (MDR) human A549 lung cancer cells (A549RT-eto) with the elevated expression of NF-κB showed epithelial-mesenchymal transition (EMT), increasing spheroid formation and elevating the expression levels of stemness-related factors, including Oct4, Nanog, Sox2, Bmi1, and Klf4. Therefore, when new therapeutic agents targeting these malignant cancer cells were explored, we found that caged-xanthone (CX) isolated from the roots of Cratoxylum formosum ssp. pruniflorum diminished the expression of NF-κB, P-glycoprotein (P-gp) protein levels, cell migration and invasion, and sphere-forming ability of A549RT-eto cells. To address the role of NF-κB in these malignant cancer features, we treated A549RT-eto cells with NF-κB siRNAs in the present work. We found that the knockdown of NF-κB inhibited EMT and sphere formation. Furthermore, co-treatment with CX and NF-κB siRNA accelerated the death of apoptotic cells through the decrease of P-gp protein levels. These results suggest that NF-κB was involved in malignant cancer phenotypes and MDR in A549RT-eto cells. Taken together, our findings suggest that CX can be a potential therapeutic agent for the treatment of malignant tumor cells.

Formoxanthone C, isolated from Cratoxylum formosum ssp. pruniflorum, reverses anticancer drug resistance by inducing both apoptosis and autophagy in human A549 lung cancer cells.

Multidrug resistance (MDR) cancer toward cancer chemotherapy is one of the obstacles in cancer therapy. Therefore, it is of interested to use formoxanthone C (1,3,5,6-tetraoxygenated xanthone; XanX), a natural compound, which showed cytotoxicity against MDR human A549 lung cancer (A549RT-eto). The treatment with XanX induced not only apoptosis- in A549RT-eto cells, but also autophagy-cell death. Inhibition of apoptosis did not block XanX-induced autophagy in A549RT-eto cells. Furthermore, suppression of autophagy by beclin-1 small interfering RNAs (siRNAs) did not interrupt XanX-induced apoptosis, indicating that XanX can separately induce apoptosis and autophagy. Of interest, XanX treatment reduced levels of histone deacetylase 4 (HDAC4) protein overexpressed in A549RT-etocells. The co-treatment with XanX and HDAC4 siRNA accelerated both autophagy and apoptosis more than that by XanX treatment alone, suggesting survival of HDAC4 in A549RT-eto cells. XanX reverses etoposide resistance in A549RT-eto cells by induction of both autophagy and apoptosis, and confers cytotoxicity through down-regulation of HDAC4.

Antibacterial, anti-inflammatory and anti-oxidatant activities of various isolated compounds from Cratoxylum species.

The objective of this study was to investigate the bioactivity of twenty-nine known isolated compounds from Cratoxylum species including three anthraquinones, four triterpenes, and twenty-two xanthones. All isolated compounds were subjected to antibacterial, anti-inflammatory and anti-oxidant activities. Cytotoxicity evaluations were performed by MTT assay. The anti-oxidatant activity was performed using DPPH assay. The anti-inflammatory activity was evaluated from the production of cytokines TNF-α and IL1-ß using ELISA assay. Human gingival fibroblasts and monocytes could tolerate both anthraquinones and triterpenes. All isolated anthraquinones showed moderate-to-high antibacterial efficacy while compound A3 also demonstrated moderate anti-inflammatory effect. None of the isolated triterpenes, except for T1, inhibited the expression of TNF-α. A number of isolated xanthones was toxic to HGFs and monocytes. Compound X5, X14 and a 1:1 mixture of X5 and X6 showed comparative anti-inflammatory activity to dexamethasone. Several triterpene and xanthone compounds also expressed antibacterial effect against P. gingivalis. Some isolated xanthones exerted anti-oxidant activity comparable to ascorbic acid. Accordingly, selected pure compounds from plants of Cratoxylum genus might be of benefit in developing medications that are important in treating periodontal diseases.

Anti-HIV-1 integrase activity and molecular docking of compounds from Albizia procera bark.

CONTEXT: Albizia procera (Roxb.) Benth. (Mimosaceae) has been traditionally used in Thai longevity preparations. Thus, searching for HIV-1 integrase (HIV-1 IN) agents from natural sources is of interest. OBJECTIVE: The objective of this study is to examine the inhibitory activity against HIV-1 IN of compounds isolated from the stem bark of Albizia procera. MATERIALS AND METHODS: The EtOH extract and isolated compounds of Albizia procera bark were examined for anti-HIV-1 IN activity at various concentrations (10-100 µg/mL and 10-100 µM) using the multiplate integration assay and molecular docking. RESULTS AND DISCUSSIONS: The results showed that the ethanol extract had good anti-HIV-1 IN activity with an IC50 value of 19.5 µg/mL, whereas ethyl acetate fraction exhibited the most potent with an IC50 value of 19.1 µg/mL, followed by water fraction (IC50 value = 21.3 µg/mL), hexane and chloroform fractions (IC50 value > 100 µg/mL), respectively. From bioassay-guided isolation, the ethyl acetate fraction was further separated to give two compounds which are (+)-catechin (1) and protocatechuic acid (2), respectively. Of the tested samples, (+)-catechin (1) exhibited appreciable activity against HIV-1 IN with an IC50 value of 46.3 µM, whereas protocatechuic acid (2) showed mild activity with 46.0% inhibition at concentration of 100 µM. (+)-Catechin (1) could interact with Thr66, Gly148, and Glu152 in the core domain of IN enzyme, whereas protocatechuic acid (2) could bind with Thr66, His67, Glu152, Asn155, and Lys159. This is the first report on anti-HIV-1 IN activity of Albizia procera bark. These results may suggest that Albizia procera bark has potential as anti-HIV-1 IN agent.

Three types of cytotoxic natural caged-scaffolds: pure enantiomers or partial racemates.

Two rare new natural products, the neocaged-xanthone pruniflorone T (1) and the rearranged caged-xanthone pruniflorone U (3), and the known caged-xanthone cochinchinone C (2) were isolated from the roots of Cratoxylum formosum ssp. pruniflorum. The unique structures of 1-3 were determined by analysis of NMR and X-ray diffraction data. The X-ray data of 1-3 revealed that they all exist with both enantiomers in their crystal packing. Separation of 1-3 by chiral HPLC led to the isolation of three pairs of enantiomers, (-)-1/(+)-1, (-)-2/(+)-2, and (-)-3/(+)-3, and their absolute configurations were determined by analysis of single-crystal X-ray diffraction and ECD spectroscopic data. A 1:1 mixture of 1 and 3 showed potent in vitro cytotoxicity against an MCF-7 human breast cancer cell line with an IC50 value of 0.11 µg/mL.

2,2'-[2,4-Bis(naphthalen-1-yl)cyclo-butane-1,3-di-yl]bis-(1-methyl-pyridinium) bis-(4-chloro-benzene-sulfonate): thermal-induced [2 + 2] cyclo-addition reaction of a heterostilbene.

The asymmetric unit of the title salt, C36H32N2 (2+)·2C6H4ClO3S(-), consists of one anion and one half-cation, the other half being generated by inversion symmetry. The dihedral angle between the pyridinium ring and the napthalene ring system in the asymmetric unit is 42.86 (6)°. In the crystal, cations and anions are linked by weak C-H⋯O inter-actions into chains along [010]. Adjacent chains are further arranged in an anti-parallel manner into sheets parallel to the bc plane. π-π inter-actions are observed involving the cations, with centroid-centroid distances of 3.7664 (8) and 3.8553 (8) Å.

(E)-2-[(2,4,6-Tri-meth-oxy-benzyl-idene)amino]-phenol.

There are two independent mol-ecules in the asymmetric unit of the title compound, C16H17NO4, with similar conformations but some differences in their bond angles. Each mol-ecule adopts a trans configuration with respect to the methyl-idene C=N bond and is twisted with a dihedral angle between the two substituted benzene rings of 80.52 (7)° in one mol-ecule and 83.53 (7)° in the other. All meth-oxy groups are approximately coplanar with the attached benzene rings, with Cmeth-yl-O-C-C torsion angles ranging from -6.7 (2) to 5.07 (19)°. In the crystal, independent mol-ecules are linked together by O-H⋯N and O-H⋯O hydrogen bonds and a π-π inter-action [centroid-centroid distance of 3.6030 (9) Å], forming a dimer. The dimers are further linked by weak C-H⋯O inter-actions and another π-π inter-action [centroid-centroid distance of 3.9452 (9) Å] into layers lying parallel to the ab plane.

(E)-4-Meth-oxy-N'-(2,4,5-tri-meth-oxy-benzyl-idene)benzohydrazide hemihydrate.

The title compound crystallizes as a hemihydrate, C18H20N2O5·0.5H2O. The mol-ecule exists in an E conformation with respect to the C=N imine bond. The 4-meth-oxy-phenyl unit is disordered over two sets of sites with a refined occupancy ratio of 0.54 (2):0.46 (2). The dihedral angles between the benzene rings are 29.20 (9) and 26.59 (9)°, respectively, for the major and minor components of the 4-meth-oxy-substituted ring. All meth-oxy substituents lie close to the plane of the attached benzene rings [the Cmeth-yl-O-C-C torsion angles range from -4.0 (12) to 3.9 (2)°]. In the crystal, the components are linked into chains propagating along [001] via N-H⋯O and O-H⋯O hydrogen bonds and weak C-H⋯O inter-actions.

(E)-2-[4-(Di-ethyl-amino)-styr-yl]-1-methyl-quinolin-1-ium 4-chloro-benzene-sulfonate monohydrate.

The asymmetric unit of the title hydrated salt, C22H25N2 (+)·C6H4ClO3S(-)·H2O, comprises two 2-[4-(di-ethyl-amino)-styr-yl]-1-methyl-quinolin-1-ium cations, two 4-chloro-benzene-sul-fon-ate anions and two solvent water mol-ecules. One ethyl group of both cations displays disorder over two positions in a 0.659 (2):0.341 (2) ratio in one mol-ecule and in a 0.501 (2):0.499 (2) ratio in the other. The sulfonate group of one anion is also disordered over two positions in a 0.893 (7):0.107 (7) ratio. The dihedral angle between the mean plane of the quinolinium ring system and that of benzene ring is 10.57 (18)° in one cation and 14.4 (2)° in the other. In the crystal, cations, anions and water mol-ecules are linked into chains along the [010] direction by O-H⋯Osulfonate hydrogen bonds, together with weak C-H⋯Osulfonate and C-H⋯Cl inter-actions. The cations are stacked by π-π inter-actions, with centroid-centroid distances in the range 3.675 (2)-4.162 (3) Å.

1-(2,4-Di-nitro-phen-yl)-2-[(E)-(3,4,5-tri-meth-oxy-benzyl-idene)]hydrazine.

Mol-ecules of the title compound, C16H16N4O7, are not planar with a dihedral angle of 5.50 (11)° between the substituted benzene rings. The two meta-meth-oxy groups of the 3,4,5-tri-meth-oxy-benzene moiety lie in the plane of the attached ring [Cmeth-yl-O-C-C torsion angles -0.1 (4)° and -3.7 (3)°] while the para-meth-oxy substituent lies out of the plane [Cmeth-yl-O-C-C, -86.0 (3)°]. An intra-molecular N-H⋯O hydrogen bond involving the 2-nitro substituent generates an S(6) ring motif. In the crystal structure, mol-ecules are linked by weak C-H⋯O inter-actions into screw chains, that are arranged into a sheet parallel to the bc plane. These sheets are connected by π-π stacking inter-actions between the nitro and meth-oxy substituted aromatic rings with a centroid-centroid separation of 3.9420 (13) Å. C-H⋯π contacts further stabilize the two-dimensional network.

Andrographolide targets EGFR to impede epithelial-mesenchymal transition in human breast cancer cells.

Despite the primary surgical treatment for breast cancer patients, malignant invasiveness and metastasis remain threatening factors for women with breast cancer. As chemotherapy yields unsatisfactory results, it prompted us to search for effective natural agents with few side-effects. Although andrographolide (ADGL), a natural diterpenoid lactone isolated from Andrographis paniculata, presents anticancer effects, the molecular mechanism remains unknown. Initially, on comparing the expression of proteins related to epithelial-mesenchymal transition (EMT) between nonmetastatic cancer MCF7 cells and highly metastatic cancer MDA-MB-231 cells, we found that MDA-MB-231 cells exhibit higher protein levels of N-cadherin and vimentin and lower protein levels of E-cadherin when compared to MCF7 cells. Moreover, MDA-MB-231 cells also exhibited higher EGFR expression and activity, higher STAT1 activity and abundant HDAC4 expression. To elucidate whether these proteins are closely associated with EMT, EGFR, STAT1 or HDAC4, the proteins were silenced in MDA-MB-231 breast cancer cells by their specific siRNAs. We found that silencing these proteins reduced EMT, indicating an important role of EGFR, STAT1 and HDAC4 in EMT progression. When we treated MDA-MB-231 cells with ADGL as a potential therapeutic drug, we found that ADGL treatment inhibited cell migration and invasion. Furthermore, it also recovered E-cadherin expression and decreased N-cadherin and vimentin protein levels. ADGL treatment reduced EGFR expression at a lower concentration (1 µg/mL); however, STAT1 activity and HDAC4 expression was reduced by a higher concentration (5 µg/mL) of ADGL. Moreover, we observed that the combined treatment with ADGL and siRNAs against these proteins highly sensitized the MDA-MB-231 cells to apoptosis compared to that with ADGL and control siRNA. Collectively, our results suggest that ADGL targets EGFR, thereby inhibiting EMT in human breast cancer cells.

(E)-1-(2-Amino-phen-yl)-3-(thio-phen-2-yl)prop-2-en-1-one.

The mol-ecule of the title heteroaryl chalcone derivative, C13H11NOS, exists in a trans-configuaration and is almost planar with a dihedral angle of 3.73 (8)° between the phenyl and thio-phene rings. An intra-molecular N-H⋯O hydrogen bond generates an S(6) ring motif. In the crystal, two adjacent mol-ecules are linked into a dimer in an anti-parallel face-to-face manner by a pair of C-H⋯O inter-actions. Neighboring dimers are further linked into chains along the c-axis direction by N-H⋯N hydrogen bonds.

(2E)-1-(Pyridin-2-yl)-3-(2,4,5-tri-meth-oxy-phen-yl)prop-2-en-1-one.

The title heteroaryl chalcone derivative, C17H17NO4, is close to planar: the dihedral angle between the pyridine and benzene rings is 3.71 (11)° and the meth-oxy C atoms deviate from their attached ring by 0.046 (3), -0.044 (2) and 0.127 (3) Å. The disposition of the pyridine N atom and the carbonyl group is anti [N-C-C-O = -177.7 (2)°]. In the crystal, mol-ecules are linked by weak C-H⋯N and C-H⋯O inter-actions into (100) sheets and an aromatic π-π stacking inter-action between the pyridine and benzene ring, with a centroid-centroid separation of 3.7036 (14) Šalso occurs.

Poly[µ5-(4-meth-oxy-benzene-sulfonato)-sodium].

In the title complex, [Na(C7H7O4S)] n , the Na(I) ion is coord-inated in a slightly distorted penta-gonal-bipyramidal environment by seven O atoms [Na-O = 2.3198 (16)-2.5585 (17) Å]. The 4-methoxybenzenesulfonate anions act as bis-chelating and bridging ligands, forming a two-dimensional polymer parallel to (001), which is further linked into a three-dimensional network by weak C-H⋯O hydrogen bonds.

Racemic 2'-hydroxy-4',4'-dimethylpyran-1,5-dihydroxyxanthone monohydrate.

THE TITLE XANTHONE (SYSTEMATIC NAME: 3,6,11-trihy-droxy-1,1-dimethyl-2,3-di-hydro-chromeno[2,3-f]chromen-7-one monohydrate), known as pruniflorone N, crystallized as a monohydrate, C18H16O6·H2O. The three ring systems of the xanthone skeleton are approximately coplanar, with an r.m.s. deviation of 0.0270 (1) Šfrom the plane through the 14 non-H atoms. The O atoms of the two hy-droxy substituents on the benzene rings also lie close to this plane, with deviations of 0.019 (1) and 0.070 (1) Å. The 2'-hy-droxy-4',4'-di-methyl-pyran ring is disordered over two positions with a 0.798 (3):0.202 (3) site-occupancy ratio. An intra-molecular O-H⋯O hydrogen bond generates an S(6) ring motif. In the crystal, the xanthone and water mol-ecules are linked into a three-dimensional network by O-H⋯O hydrogen bonds and weak C-H⋯O inter-actions. π-π inter-actions, with centroid-centroid distances of 3.5982 (7), 3.6081 (7) and 3.6456 (7) Å, are also observed.

2-[(E)-2-(4-Hy-droxy-3-meth-oxy-phen-yl)ethen-yl]-1-methylpyridinium 4-bromo-benzene-sulfonate monohydrate.

The title salt crystallized as the monohydrate C15H16NO2 (+)·C6H4BrSO3 (-)·H2O. The cation exists in an E conformation with respect to the ethynyl bond and is essentially planar, with a dihedral angle of 6.52 (14)° between the pyridinium and the benzene rings. The hy-droxy and meth-oxy substituents are coplanar with the benzene ring to which they are attached, with an r.m.s. deviation of 0.0116 (3) Šfor the nine non-H atoms [Cmeth-yl-O-C-C torsion angle = -0.8 (4)°]. In the crystal, the cations and anions are stacked by π-π inter-actions, with centroid-centroid distances of 3.7818 (19) and 3.9004 (17) Å. The cations, anions and water mol-ecules are linked by O-H⋯O hydrogen bonds and weak C-H⋯O inter-actions, forming a three-dimensional network.

4-[(E)-(4-Eth-oxy-benzyl-idene)amino]-phenol.

The mol-ecule of the title compound, C15H15NO2, adopts a trans conformation with respect to the methyl-idene C=N bond and is twisted with a dihedral angle of 26.31 (5)° between the two substituted benzene rings. The eth-oxy group is almost coplanar with the bound benzene ring with a C-O-C-C torsion angle of -179.08 (9)°. In the crystal, mol-ecules are linked by O-H⋯N hydrogen bonds and weak C-H⋯O inter-actions into chains propagating in the [011] and [01-1] directions. C-H⋯π inter-actions are also present.