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.

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.

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.

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.

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.

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).

Polyprenylated benzophenone derivatives with a novel tetracyclo[8.3.1.03,11.05,10]tetradecane core skeleton from Clusia burle-marxii exhibited cytotoxicity against GL-15 glioblastoma-derived human cell line.

Three new polyprenylated benzophenone derivatives (1-3) were identified in the hexane extract of Clusia burle-marxii trunks, through the isolation and structural elucidation of their methyl derivatives, along with two known polyprenylated benzophenone derivatives sampsonine N (4) and obdeltifolione C (5). Burlemarxiones A (1) and B (2) show an unprecedent tetracyclo[8.3.1.03,11.05,10]tetradecane core skeleton. These compounds are a pair of ß-diketones in tautomeric equilibrium, whereas isonemorosonol (3) is the respective ß-diketone pair in tautomeric equilibrium with nemorosonol. Burlemarxione A methyl derivative (1a) and sampsonine N exhibited strong in vitro cytotoxic activity against GL-15 glioblastoma-derived human cell line.

Four new metabolites from the endophytic fungus Diaporthe lithocarpus A740.

One new benzophenone derivative, named tenllone I (1), two new eremophilane derivatives lithocarins B (2) and C (3), and a new monoterpentoid lithocarin D (4), together with two know compounds (5 and 6) were isolated from the endophytic fungus Diaporthe lithocarpus A740. All of the structures for these new compounds were fully characterized and established on the basis of extensive spectroscopic interpretation. In addition, all the isolated compounds were evaluated in vitro for their cytotoxic activity. Compounds 2, 3, and 5 showed weak inhibitory activities against tumor cell lines.

Effects of Benzophenones from Mango Leaves on Lipid Metabolism.

The mango tree (Mangifera indica L.) is a tropical, perennial, woody evergreen plant belonging to the Anacardiaceae. In traditional medicine, dried mango tree leaves were considered useful in treating diabetes and respiratory infections. In this paper, we review the phytochemical research on mango leaves and the mechanisms of benzophenones in lipid metabolism regulation. Thirty-six benzophenones have been isolated from mango leaves; among them, mangiferin is the major compound. Structure-activity relationships of benzophenones in lipid accumulation and the mechanisms of action of mangiferin in lipid metabolism are summarized. After oral administration, mangiferin is partly converted to its active metabolite, northyariol, which contributes to the activation of sirtuin-1 and liver kinase B1 and increases the intracellular AMP level and AMP/adenosine triphosphate ratio, followed by AMP-activated protein kinase phosphorylation, leading to increased phosphorylation of sterol regulatory element-binding protein-1c. Current evidence supports ethnopharmacological uses of mango leaves in diabetes and points toward potential future applications.

Identification of a new benzophenone from Psidium guajava L. leaves and its antineoplastic effects on human colon cancer cells.

Psidium guajava L. leaves have a long history of being consumed as herbal teas in many countries. The aim of this study was to identify compounds with anticancer potentials from Psidium guajava L. leaves. Utilizing various extraction and chromatographical techniques, we have isolated one new (2) and two known compounds (1, 3). Structural analyses by the spectroscopic methods of TOF-MS, 1H NMR, 13C NMR, HSQC, and HMBC identified these three compounds as guavinoside E (1), 3,5-dihydroxy-2,4-dimethyl-1-O-(6'-O-galloyl-ß-d-glucopyranosyl)-benzophenone (2), and guavinoside B (3). Cell viability assays showed that compounds 2 and 3 inhibited the growth of HCT116 human colon cancer cells in a dose-dependent manner, where compound 2 was more potent than compound 3. Based on flow cytometry analysis, compound 2 showed stronger activity in inducing cellular apoptosis in cancer cells than compound 3. Furthermore, compounds 2 and 3 modulated expression levels of key proteins involved in cell proliferation and apoptotic signaling. Specifically, compound 2 increased the levels of p53, p-ERK1/2, p-JNK, and cleaved caspases 8 and 9, and compound 3 increased the levels of p53 and cleaved caspase 8. Overall, this study provided identities of three bioactive compounds from P. guajava L. leaves and their anti-cancer effects against human colon cancer cells, which could facilitate the utilization of these compounds and P. guajava L. leaves as potential chemoprevention agents against colon carcinogenesis.

Membrane selection and optimisation of tangential flow ultrafiltration of Cyclopia genistoides extract for benzophenone and xanthone enrichment.

Ultrafiltration of Cyclopia genistoides extract was optimised to increase its benzophenone and xanthone content as quantified using HPLC-DAD. Regenerated cellulose (RC) and polyethersulphone membranes with molecular weight cut-offs of 10 and 30 kDa were evaluated in terms of compound enrichment, permeate flux and permeate yield, using dead-end ultrafiltration. Compound enrichment was subsequently optimised using the 10 kDa RC membrane and tangential flow ultrafiltration (TFU). The effect of extract composition on compound enrichment, due to natural variation in the source material, was assessed using extracts from different batches of plant material (n = 11). Transmembrane pressure and feed flow rate affected (p < 0.05) process efficiency (mean permeate flux, compound enrichment and membrane fouling). TFU achieved ≥20% enrichment of the target compounds, proving its suitability for preparation of a nutraceutical extract of C. genistoides.

[A new benzophenone isolated from fibrous roots of Anemarrhena asphodeloides].

Five compounds were isolated from the fibrous roots of Anemarrhena asphodeloides by silica gel, Sephadex LH-20 and semi-HPLC column chromatography. On the basis of physic-chemical properties and spectroscopic data analysis, these compounds were identified as methyl 2-[2,4-dihydroxy-3-(4-hydroxybenzoyl)-6-methoxyphenyl]acetate(1), 4-[formyl-5-(methoxymethyl)-1H-pyrrol-1-yl]butanoate(2), perlolyrine(3),syringaresinol-4'-O-ß-D-glucoside(4) and 4',6-dihydroxy-4-methoxybenzophenone-2-O-(2″),3-C-(1″)-1″-desoxy-α-L-fructofuranoside(5). Among them, 1 was a new benzophenone. Compounds 2-5 were isolated from this plant for the first time. Compound 1 was tested for neuroprotective effects against H_2O_2-induced damage in SH-SY5 Y cells.

Two new benzophenones and one new natural amide alkaloid isolated from a mangrove-derived Fungus Penicillium citrinum.

Two new compounds penibenzophenones A-B (1-2), and the synthetic α,ß-unsaturated amide alkaloid (E)-tert-butyl(3-cinnamamidopropyl)carbamate (4), newly identified as a natural product, alone with three known ones (3, 5-6) were isolated from the EtOAc extract of the endophytic fungus Penicillium citrinum HL-5126 isolated from the mangrove Bruguiera sexangula var. rhynchopetala collected in the South China Sea. Compound 1 was a chlorinated benzophenone. The structures of 1-6 were elucidated by extensive NMR spectral interpretation, MS data and X-ray analysis. The new compound 2 displayed cytotoxic activity against human A549 cell lines with an IC50 value of 15.7 µg/mL, and 1 showed antibacterial activity against Staphylococcus aureus with a MIC value of 20 µg/mL.

Guttiferone BL with antibacterial activity from the fruits of Allanblackia gabonensis.

Allanblackia genus, an endless source of bioactive compounds, was investigated for its antibacterial properties. The chemical study of the methanol extract from the fruits of Allanblackia gabonensis resulted in the isolation of the undescribed guttiferone BL (1) along with the known kaempferol (2), morelloflavone (3), morelloflavone 7″-O-ß-D-glucopyranoside (4), ß-sitosterol 3-O-ß-D-glucopyranoside and ß-sitosterol. Their structures were determined using spectrometry and spectroscopic techniques. The antibacterial activity was evaluated against five Gram-negative and two Gram-positive strains using a broth micro-dilution method. Compounds displayed low to significant activity against the tested bacterial strains with MICs ranging from 8 to 512 µg/mL. Morelloflavone (3) presented significant activity against E. coli ATCC8739 (MIC = 8 µg/mL) while guttiferone BL (1) exhibited low activity (MICs = 256-512 µg/mL) against all the tested strains. The crude extract also had moderate to significant activity against the tested bacterial strains.

Benzophenone glycosides from the flower buds of Aquilaria sinensis.

Four new benzophenone glycosides named as aquilaside A-D (1-4) along with five known compounds (5-9) were isolated from the methanol extract of the flower buds of Aquilaria sinensis. Their structures were elucidated on the basis of 1D and 2D NMR and mass spectroscopic analyses. All purified compounds were evaluated for their anti-inflammatory and cytotoxic activities. Aquilasides B and C displayed moderate cytotoxicity against SK-MEL cells with IC50 of 17.0 and 12.0µM and weak NF-κB inhibitive activity at 100µM with 30% and 60%, respectively.

Separation and preparation of xanthochymol and guttiferone E by high performance liquid chromatography and high speed counter-current chromatography combined with silver nitrate coordination reaction.

Xanthochymol (XCM) and guttiferone E (GFE), a pair of π bond benzophenone isomers from Garcinia xanthochymus, were once reported to be difficult or impossible to separate. The present study reports the successful separation of these two isomers through high performance liquid chromatography (HPLC), as well as their effective isolation using high speed counter-current chromatography (HSCCC) based on the silver nitrate (AgNO3) coordination reaction. First, an effective HPLC separation system was developed, achieving a successful baseline separation with resolution of 2.0. Based on the partition coefficient (K) resolved by HPLC, the two-phase solvent system was determined as n-hexane, methanol and water with the uncommon volume ratio of 4:6:1. A crude extract of Garcinia xanthochymus (0.2g) was purified by normal HSCCC and refined with AgNO3-HSCCC. Monomers of XCM and GFE were identified by HPLC, mass spectrometry (MS) and nuclear magnetic resonance (NMR). The results demonstrate the separation and isolation of π bond benzophenone isomers using ordinary octadecyl silane (C18) columns and HSCCC.

A new benzophenone glycoside from the leaves of Mitracarpus villosus.

A new benzophenone glycoside, mitraphenone A (1), together with three known compounds (2-4) were isolated from the leaves of the traditionally used medicinal plant Mitracarpus villosus (Rubiaceae) collected in Nigeria. A combination of one- and two-dimensional NMR spectroscopic and mass spectrometric measurements were carried out to identify the structure of 1. All isolated compounds (1-4) were screened for their antibacterial activity against several Gram-positive and Gram-negative bacteria. Compound 1 exhibited moderate activity against Enterococcus faecium (strains ATCC 35667 and ATCC 700221) and Staphylococcus aureus ATCC 25923 with MIC values ranging from 25 to 50 µM.

Three new highly-oxygenated metabolites from the endophytic fungus Cytospora rhizophorae A761.

Cytosporaphenones A-C, one new polyhydric benzophenone and two new naphtopyrone derivatives, along with eight known ones, were isolated from Cytospora rhizophorae, an endophytic fungus from Morinda officinalis. Their structures were fully characterized by means of detailed spectroscopic analysis and X-ray single crystal diffraction. To our knowledge, the three new compounds were the most highly oxygenated metabolites of their families discovered in nature. Moreover, all of the compounds were evaluated for in vitro cytotoxic activities against MCF-7, NCI-H460, HepG-2 and SF-268 tumor cell lines, and the new compound 1 exhibited weak growth inhibitory activity against the tumor cell lines MCF-7 and HepG-2 with IC50 values of 70 and 60µM, respectively.

A possible glycosidic benzophenone with full substitution on B-ring from Psidium guajava leaves.

Bidimensional NMR analysis may be a useful tool to resolve the structure of chemical compounds also in mixture. This letter would demonstrate how these techniques could be applied e.g. to the reported case on identification of benzophenone glycoside from Psidium guajava. A tentative structure for the secondary component, not yet described, was possibly proposed on the basis of observation and critic review of available 1D and 2D NMR spectra.

Chiral separation and absolute configurations of two pairs of racemic polyprenylated benzophenones from Hypericum sampsonii.

(±) Sampsonins A-B (1-2), two pairs of racemic polyprenylated benzophenones, were isolated from the aerial parts of Hypericum sampsonii and successfully separated by chiral HPLC column. Their structures were elucidated by spectroscopic analyses, X-ray diffraction analysis, and quantum chemical calculation of ECD method. Besides, the plausible biogenetic pathways of 1-2 were proposed, and all of them were evaluated for RXRα transcriptional-inhibitory activities and cytotoxicity against HeLa cells.