Anti-inflammatory Dimeric Benzophenones from an Endophytic Pleosporales Species.

Eight new polyketides, including three dimeric benzophenones, named dipleosporones A-C (1-3), three benzophenones (4-6), one xanthone (7), and one phenylbenzoate (8), along with seven known polyketides (9-15) were isolated from the fungus Pleosporales sp. YY-4. The structures of the new compounds were established on the basis of spectroscopic methods, including high-resolution electrospray ionization mass spectrometry and one- and two-dimensional nuclear magnetic resonance. This is the first report of a benzophenone dimer connection via a C bridge from natural sources. An anti-inflammatory assay indicated that the dimeric benzophenones (1-3) inhibited lipopolysaccharide-induced NO production in RAW 264.7 cells, with half-maximal inhibitory concentration (IC50) values ranging from 8.8 to 18.1 µM, being more potent than the positive control, dexamethasone (IC50 = 22.2 µM).

Xanthones and benzophenones isolated from the endophytic fungus Penicillium sp. ct-28 of Corydlis tomentella and their cytotoxic activity.

One new xanthone, griseophenexanthone A (1), one new benzophenone, digriseophene A (2), and 14 previously reported compounds were isolated from the culture of Penicillium sp. ct-28, an endophytic fungus of Corydlis tomentella. The structures of the isolated compounds were identified by an extensive analysis of HRESIMS, 1D and 2D NMR. MTT assay showed that six xanthones (1 and 3-7) significantly inhibited cell proliferation in four cancer cell lines, with IC50 values ranging from 18.12 ± 2.42 to 85.55 ± 7.66 µM. Our results showed that slight structural changes led to obvious activity differences among these compounds. We also investigated the effects of the six xanthones on cell cycle and apoptosis in human hepatoma HepG2 cells. Compound 7 caused cell cycle arrest at G1 phase, compounds 5 and 6 caused cell cycle arrest at S phase, whereas compounds 1, 3 and 4 had no effects on cell cycle distribution. All six xanthones induced apoptosis in dose-dependent manners in HepG2 cells accompanied by degradation of PARP and activation of caspase 3. The structure-activity relationship analysis revealed that the effects of these xanthones on cell cycle and apoptosis in HepG2 cells were closely related to the substituent groups on their skeleton. Our studies provide novel insights for the structural optimization of xanthones in the development of new anticancer drugs.

Benzophenone Glucosides and B-Type Proanthocyanidin Dimers from Zambian Cassia abbreviata and Their Trypanocidal Activities.

Two benzophenone glucosides (1 and 2), five flavan-3-ol dimers (5-9), and 17 known compounds (3, 4, and 10-24) were identified from the bark extract of Cassia abbreviata. The chemical structures display two points of interest. First, as an unusual characteristic feature of the 1H NMR spectra of 1 and 2, the signals for the protons on glucosidic carbons C-2 are shielded as compared to those generally observed for glucosyl moieties. The geometrically optimized 3D structures derived from conformational analysis and density functional theory (DFT) calculations revealed that this shielding effect originates from intramolecular hydrogen bonds in 1 and 2. Additionally, 3-15 were identified as dimeric B-type proanthocyanidins, which have 2R,3S-absolute-configured C-rings and C-4-C-8″ linkages, as evidenced by X-ray crystallography and by NMR and ECD spectroscopy. These results suggest the structure-determining procedures for some reported dimers need to be reconsidered. The trypanocidal activities of the isolated compounds against Trypanosoma brucei brucei, T. b. gambiense, T. b. rhodesiense, T. congolense, and T. evansi were evaluated, and the active compounds were identified.

Two new benzophenones isolated from a mangrove-derived fungus Penicillium sp.

One new benzophenone derivative, named penibenzophenone C (1), and a new benzophenone natural product, neamed penibenzophenone D (2), together with two known compounds (3, 4) were isolated from the EtOAc extract of the endophytic fungus Penicillium sp. isolated from the mangrove Acanthus ilicifolius L. collected in the South China Sea. The structures of 1-4 were elucidated by extensive NMR spectral interpretation and MS data. The new compounds 1 and 2 showed moderate antibacterial activities against methicillin-resistant Staphylococcus aureus with the MIC values of 3.12 and 6.25 µg ml-1, respectively.

Effectiveness and Anticancer Activity of a Novel Phenolic Compound from Garcinia porrecta Against the MCF-7 Breast Cancer Cell Line in vitro and in silico.

BACKGROUND: Cancer is a leading cause of death worldwide, with breast cancer being the most common invasive cancer type in women. Several therapeutic strategies have been explored to reduce the mortality rates of breast cancer. Chemotherapy is the most commonly used systemic treatment, but associated with numerous side-effects. Development of anticancer agents with high efficacy and minimal negative effects is therefore an important focus of research. Natural materials provide an excellent source of bioactive compounds. For instance, Garcinia porrecta from the Clusiaceae family has multiple pharmacological activities, including antioxidant, anti-inflammatory, antibacterial, antiviral, anti-HIV, antidepressant, and anticancer properties. PURPOSE: The main objective of this study was to investigate the potential anticancer effects of compounds extracted from the bark of G. porrecta. MATERIALS AND METHODS: Our experiments were divided into three steps: (1) chromatographic isolation of compounds using various separation techniques, such as extraction, separation and purification, (2) characterization via infrared (IR), nuclear magnetic resonance (NMR) and mass spectroscopy, and (3) evaluation of anticancer activity in vitro (MTT assay) and in silico (via analysis of molecular docking against caspase-9, tumor necrosis factor alpha (TNF-α), estrogen receptor alpha (ER-α), and human epidermal growth factor receptor 2 (HER-2)). RESULTS: Depsidone (1) and benzophenone (2) from the ethyl acetate extract of bark of G. porrecta were identified as bioactive components. Examination of the activities of these compounds against MCF-7 cells revealed an IC50 value of 119.3 µg/mL for benzophenone, whereas IC50 for depsidone could not be estimated. Benzophenone activity was lower than that of the positive control doxorubicin (6.9 µg/mL). Depsidone showed the highest binding affinity for HER-2 (-9.2 kcal.mol-1) and benzophenone for ER-α (-8.0 kcal.mol-1). CONCLUSION: Benzophenone displays potency as an anticancer agent through blocking ER-α.

Green and Red Brazilian Propolis: Antimicrobial Potential and Anti-Virulence against ATCC and Clinically Isolated Multidrug-Resistant Bacteria.

Brazilian green and red propolis stand out as commercial products for different medical applications. In this article, we report the antimicrobial activities of the hydroalcoholic extracts of green (EGP) and red (ERP) propolis, as well as guttiferone E plus xanthochymol (8) and oblongifolin B (9) from red propolis, against multidrug-resistant bacteria (MDRB). We undertook the minimal inhibitory (MIC) and bactericidal (MBC) concentrations, inhibition of biofilm formation (MICB50 ), catalase, coagulase, DNase, lipase, and hemolysin assays, along with molecular docking simulations. ERP was more effective by displaying MIC and MBC values <100 µg mL-1 . Compounds 8 and 9 displayed the lowest MIC values (0.98 to 31.25 µg mL-1 ) against all tested Gram-positive MDRB. They also inhibited the biofilm formation of S. aureus (ATCC 43300 and clinical isolate) and S. epidermidis (ATCC 14990 and clinical isolate), with MICB50 values between 1.56 and 6.25 µg mL-1 . The molecular docking results indicated that 8 and 9 might interact with the catalase's amino acids. Compounds 8 and 9 have great antimicrobial potential.

Benzophenones from Betula alnoides with Antiausterity Activities against the PANC-1 Human Pancreatic Cancer Cell Line.

The antiausterity strategy is a promising approach for the discovery of lead compounds with unprecedented anticancer activities by targeting the tolerance of cancer cells to nutrition starvation. These agents are selectively cytotoxic under the tumor microenvironment-mimicking condition of nutrition starvation, without apparent toxicity in the normal nutrient-rich condition. In this study, an ethanol extract of Betula alnoides showed antiausterity activity against PANC-1 human pancreatic cancer cells under nutrient-deprived conditions, with a PC50 value of 13.2 µg/mL. Phytochemical investigation of this active extract led to the isolation of eight benzophenones (1-8), including six new compounds, named betuphenones A-F (2-7), and three known xanthones (9-11). The structure elucidation of the new compounds was achieved by HRFABMS, NMR, and ECD spectroscopic analyses. A plausible biogenetic pathway of the new compounds was proposed. Compounds 1-7 displayed antiausterity activity with PC50 values of 4.9-8.4 µM. Moreover, compounds 2 and 7 induced alterations in PANC-1 cell morphology under nutrient-deprived conditions and also inhibited PANC-1 colony formation under nutrient-rich conditions.

Determination of 21 photoinitiators in human plasma by using high-performance liquid chromatography coupled with tandem mass spectrometry: A systemically validation and application in healthy volunteers.

In the present study, a comprehensive and sensitive method for simultaneous determination of 21 PIs (nine benzophenones, eight amine co-initiators, and four thioxanthones) in human plasma using high-performance liquid chromatography coupled with tandem mass spectrometry was developed and validated. Two different pre-treatment approaches (liquid-liquid extraction (LLE) and LLE coupled with solid-phase extraction (SPE)) and eight extraction solvents were studied to optimize sample treatment to obtain good recoveries and reduce any matrix effects. The procedure of LLE+SPE was selected as final sample treatment procedure because it obtained higher recoveries as well as lower matrix effects than that performed by LLE alone. The recoveries of 21 target analytes at three spiked concentrations (0.05, 0.5, and 5 ng/mL) ranged from 81% to 109%. The intra- and inter-day relative standard deviations were between 2.5% and 13%. Accuracy and precision data indicated that the detection method was accurate and precise for most of the PIs. The linearities of the labeled dilution calibration curves at 10 concentration levels (iLOQ to 100 ng/mL or iLOQ to 200 ng/mL) were good with correlation coefficients ranged from 0.995 to 0.999. The method quantification limits were in the range of 1.7-16 pg/mL. The analytical method was applied to the analysis of PIs in 14 human plasma samples collected from pregnant women in Guangdong Province, China. Fifteen PIs were detected with total concentrations ranging from 318 to 2772 pg/mL. The ubiquitous contamination of human plasma with PIs suggests that there is widespread exposure to these compounds. Consequently, there should be increased awareness of these pollutants in the environment.

Novel ferulic acid and benzophenone derivatives from the flower buds of Syzygium aromaticum.

Phytochemical investigation of clove resulted in the isolation of two new natural compounds, a ferulic acid derivative, sabrinic acid (1) and a benzophenone derivative (2) together with two known compounds kaempferol-3,5-dimethyl ether (3) and 4-methyl benzoic acid (4). Compounds 3 and 4 were isolated for the first time from the genus Syzygium. The structures of compounds were elucidated through modern spectroscopic techniques including 1D and 2D NMR spectroscopy.

Multivariate optimization of low-temperature cleanup followed by dispersive solid-phase extraction for detection of Bisphenol A and benzophenones in infant formula.

A simple and effective analytical method to determine six contaminants, including five benzophenones (BP, BP-1, BP-3, BP-8, and BP-12) and bisphenol A (BPA) in infant formulas was developed in this study. For this, a sequential experimental design was used to optimize the extraction and cleanup method using low temperature partition (LTP) combined with dispersive solid phase extraction (dSPE). The effect of primary secondary amine (PSA), sodium chloride (NaCl), graphitized carbon black (GCB), octadecyl (C18), strong anion exchanger (SAX), water, acetonitrile (ACN) and, ultrasound (US) time were evaluated using a sequential design of experiments including a Plackett-Burman, a central composite rotatable design, and the Derringer and Suich's tool. The method was validated, and it showed a limit of quantification varying from 0.06 to 2 mg.kg-1, good precision (< 20% RSD), and recovery (52-106%). The method proposed was applied to twenty-five samples of commercial infant formulas.

Novel polyprenylated benzophenone derivatives from Clusia burle-marxii.

Three new caged polyprenylated benzophenone derivatives named burlemarxiones D-F (1-3) were isolated from the hexane extract of Clusia burle-marxii trunks. Burlemarxione D (1) contains the tetracyclo[8.3.1.03,11.05,10]tetradecane core skeleton also observed for burlemarxione A, its probable immediate precursor. However, two additional rings are formed to produce an unprecedented complex-caged core skeleton. These additional rings could be formed by a radical cyclization reaction of one prenyl group at C-5 with C-1 and C-33, followed by oxidative dehydrogenation (rearomatization) or by an intramolecular [4 + 2] radical cycloaddition (Diels-Alder reaction), followed by an enolization reaction (rearomatization). Burlemarxiones E and F were isolated after methylation with diazomethane that was necessary to avoid the interconversion of the pair of ß-diketones in tautomeric equilibrium. The proposed biosynthetic pathway for burlemarxiones D-F involves the condensation of either lavandulyl pyrophosphate or 2-(1-methylvinyl)-hexa-5-enyl pyrophosphate with the acylphloroglucinol derivative 6-benzoyl-5-hydroxy-5-cyclohexen-1,3-dione, followed by consecutive prenylation reactions. Therefore, Clusia burle-marxii reinforces the claim that the genus Clusia is an important source of sophisticated caged polyprenylated benzophenone derivatives.

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.

Benzophenone and Benzoylphloroglucinol Derivatives from Hypericum sampsonii with Anti-Inflammatory Mechanism of Otogirinin A.

Three new compounds, 4-geranyloxy-2-hydroxy-6-isoprenyloxybenzophenone (1), hypericumone A (2) and hypericumone B (3), were obtained from the aerial parts of Hypericum sampsonii, along with six known compounds (4-9). The structures of these compounds were determined through spectroscopic and MS analyses. Hypericumone A (2), sampsonione J (8) and otogirinin A (9) exhibited potent inhibition (IC50 values ≤ 40.32 µM) against lipopolysaccharide (LPS)-induced nitric oxide (NO) generation. Otogirinin A (9) possessed the highest inhibitory effect on NO production with IC50 value of 32.87 ± 1.60 µM. The well-known proinflammatory cytokine, tumor necrosis factor-alpha (TNF-α) was also inhibited by otogirinin A (9). Western blot results demonstrated that otogirinin A (9) downregulated the high expression of inducible nitric oxide synthase (iNOS). Further investigations on the mechanism showed that otogirinin A (9) blocked the phosphorylation of MAPK/JNK and IκBα, whereas it showed no effect on the phosphorylation of MAPKs/ERK and p38. In addition, otogirinin A (9) stimulated anti-inflammatory M2 phenotype by elevating the expression of arginase 1 and Krüppel-like factor 4 (KLF4). The above results suggested that otogirinin A (9) could be considered as potential compound for further development of NO production-targeted anti-inflammatory agent.

Targeting MHC Regulation Using Polycyclic Polyprenylated Acylphloroglucinols Isolated from Garcinia bancana.

Modulation of major histocompatibility complex (MHC) expression using drugs has been proposed to control immunity. Phytochemical investigations on Garcinia species have allowed the isolation of bioactive compounds such as polycyclic polyprenylated acylphloroglucinols (PPAPs). PPAPs such as guttiferone J (1), display anti-inflammatory and immunoregulatory activities while garcinol (4) is a histone acetyltransferases (HAT) p300 inhibitor. This study reports on the isolation, identification and biological characterization of two other PPAPs, i.e., xanthochymol (2) and guttiferone F (3) from Garcinia bancana, sharing structural analogy with guttiferone J (1) and garcinol (4). We show that PPAPs 1-4 efficiently downregulated the expression of several MHC molecules (HLA-class I, -class II, MICA/B and HLA-E) at the surface of human primary endothelial cells upon inflammation. Mechanistically, PPAPs 1-4 reduce MHC proteins by decreasing the expression and phosphorylation of the transcription factor STAT1 involved in MHC upregulation mediated by IFN-γ. Loss of STAT1 activity results from inhibition of HAT CBP/p300 activity reflected by a hypoacetylation state. The binding interactions to p300 were confirmed through molecular docking. Loss of STAT1 impairs the expression of CIITA and GATA2 but also TAP1 and Tapasin required for peptide loading and transport of MHC. Overall, we identified new PPAPs issued from Garcinia bancana with potential immunoregulatory properties.

Garcinoic Acids and a Benzophenone Derivative from the Seeds of Garcinia kola and Their Antibacterial Activities against Oral Bacterial Pathogenic Organisms.

In this study, three new garcinoic acid dimers, δ,δ-bigarcinoic acid (1), δ,δ-bi-O-garcinoic acid (2), and γ,δ-bi-O-garcinoic acid (3), and a new benzophenone derivative, (8E)-4-geranyl-3,5-dihydroxybenzophenone (4), as well as seven known compounds (5-11) were isolated from the seeds of Garcinia kola. The structures of the new compounds were elucidated using MALDI-TOF-MS and spectroscopic data, including 1D and 2D NMR and electronic circular dichroism spectra. All of the isolated compounds were evaluated for their antimicrobial activity against two oral pathogens, Porphyromonas gingivalis and Streptococcus sobrinus. Among them, 4 and δ-garcinoic acid (6) exhibited antimicrobial activity against both of these microorganisms (MICs of 31.3-62.5 µM for P. gingivalis and 15.6-31.3 µM for S. sobrinus). These results indicate that some chemical constituents in G. kola seeds have potential application in the prevention of oral diseases.

Isolation and Bioactivity of Secondary Metabolites from Solid Culture of the Fungus, Alternaria sonchi.

The fungus, Alternaria sonchi is considered to be a potential agent for the biocontrol of perennial sowthistle (Sonchus arvensis). A new chlorinated xanthone, methyl 8-hydroxy-3-methyl-4-chloro-9-oxo-9H-xanthene-1-carboxylate (1) and a new benzophenone derivative, 5-chloromoniliphenone (2), were isolated together with eleven structurally related compounds (3-13) from the solid culture of the fungus, which is used for the production of bioherbicidal inoculum of A. sonchi. Their structures were determined by spectroscopic (mostly by NMR and MS) methods. Alternethanoxins A and B, which were reported in A. sonchi earlier, were re-identified as moniliphenone and pinselin, respectively. The isolated compounds were tested for phytotoxic, antimicrobial, insecticidal, cytotoxic and esterase-inhibition activities. They did not demonstrate high phytotoxicity (lesions up to 2.5 mm in diameter/length at a concentration of 2 mg/mL) when tested on leaf disks/segments of perennial sowthistle (Sonchus arvensis) and couch grass (Elytrigia repens). They did not possess acute toxicity to Paramecium caudatum, and showed moderate to low cytotoxicity (IC50 > 25 µg/mL) for U937 and K562 tumor cell lines. However, chloromonilicin and methyl 3,8-dihydroxy-6-methyl-4-chloro-9-oxo-9H-xanthene-1-carboxylate (4) were shown to have antimicrobial properties with MIC 0.5-5 µg/disc. Compound 4 and chloromonilinic acid B were found to have contact insecticidal activity to wheat aphid (Schizaphis graminum) at 1 mg/mL. Compounds 2 and methyl 3,8-dihydroxy-6-methyl-9-oxo-9H-xanthene-1-carboxylate displayed selective carboxylesterase inhibition activity at concentration of 100 µg/mL. Therefore, the waste solid substrate for production of A. sonchi spores can be re-utilized for the isolation of a number of valuable natural products.

Glycosides of ursane-type triterpenoid, benzophenone, and iridoid from Vangueria agrestis (Fadogia agrestis) and their anti-infective activities.

Four ursane-type triterpenoid glycosides (1-4), two benzophenone glycosides (5 and 6), and one iridoid glucoside (7) were isolated and characterized from the dried roots of Vangueria agrestis. Compounds 1 (3-O-[α-L-rhamnopyranosyl-(1→2)-ß-D-xylopyranosyl]pomolic acid 28-O-ß-D-glucopyranosyl ester) and 5 (2-O-[ß-D-apiofuranosyl-(1→6)-ß-D-glucopyranosyl]-6,4'-dihydroxy-4-methoxy benzophenone) were found to be new metabolites. The identity of all compounds has been accomplished, primarily, based on 1 D and 2 D NMR and HRESMS analysis. Compounds 6 and 2, showed inhibitory effect against Trypanosoma brucei with IC50 22.3 µM for 6 and IC50 11.1 µM, IC90 12.3 µM for 2.

Benzophenone glycosides from the pericarps of Aquilaria yunnanensis S. C. Huang.

Two new benzophenone glycosides, aquilarisides A (1) and B (2), together with six known analogues (3-8) were isolated from the pericarps of Aquilaria yunnanensis S. C. Huang. Their structures were elucidated on the basis of 1D and 2D NMR and mass spectroscopic analyses, and the absolute configuration of compound 1 was determined by experimental and calculated electronic circular dichroism (ECD) spectra. Anti-inflammatory activities of all compounds 1-8 were evaluated for their inhibitory activities against lipopolysaccharide (LPS)-stimulated induced nitric oxide (NO) production in RAW 264.7 cells using the Griess assay. Compound 2 indicated a weak inhibition of NO production.

Gakolanone: a new benzophenone derivative from Garcinia kola Heckel stem-bark.

Gakolanone (3',5'-digeranyl-2',4',6',3-tetrahydroxybenzophenone; 1), a novel benzophenone derivative was isolated from the hexane extract of Garcinia kola Heckel stem-bark along with three known 3-8'' linked biflavonoids: 3'',4',4''',5,5'',7,7''-heptahydroxy-3,8''-biflavanone (2); 3'',4',5,5'',5''',7,7''-heptahydroxy-4-methoxy-3,8''-biflavanone (3) and 4',4''',5,5'',7,7''-hexahydroxy-3,8''-biflavanone (4) from the ethanol extract. The compounds were characterized primarily using 1 D and 2 D nuclear magnetic resonance spectroscopy and mass spectrometry and by comparing with literature. The compounds were subjected to in-vitro alpha-amylase enzyme inhibitory assay using DNSA (3,5-dinitrosalicylic acid) reagent with acarbose used as the standard drug. All the compounds were found to show alpha-amylase inhibitory activities with IC50 of 21.4 ± 1.5, 9.9 ± 0.2, 15.3 ± 2.3, 12.9 ± 2.3 µg/mL respectively. All the compounds exhibited better alpha-amylase inhibitory activities than the standard drug, acarbose (IC50= 38.1 ± 8.3 µg/mL).