Six unprecedented 2-(2-phenethyl)chromone dimers from agarwood of Aquilaria filaria.

Six new dimeric 2-(2-phenylethyl)chromones (1-6) were successfully isolated from the ethanol extract of agarwood of Aquilaria filaria from Philippines under HPLC-MS guidance. Compounds 1-6 are all dimers formed by linking 5,6,7,8-tetrahydro-2-(2-phenylethyl)chromone and flindersia 2-(2-phenylethyl)chromone via a single ether bond, and the linkage site (C5-O-C8'') of compound 2 is extremely rare. A variety of spectroscopic methods were used to ascertain their structures, including extensive 1D and 2D NMR spectroscopic analysis, HRESIMS, and comparison with literature. The in vitro tyrosinase inhibitory and anti-inflammatory activities of each isolate were assessed. Among these compounds, compound 2 had a tyrosinase inhibition effect with an IC50 value of 27.71 ± 2.60 µM, and compound 4 exhibited moderate inhibition of nitric oxide production in lipopolysaccharide-stimulated RAW264.7 cells with an IC50 value of 35.40 ± 1.04 µM.

A new antibacterial chromone from a marine sponge-associated fungus Aspergillus sp. LS57.

Chemical investigation for the secondary metabolite of marine-derived fungus Aspergillus sp. LS57 resulted in the isolation of one new chromone named aspergilluone A (1) containing a chromone skeleton fused with an unusual hydrogenation cyclopentanoid ring, along with three known compounds 2-4. The structure of 1 was elucidated by 1D and 2D nuclear magnetic resonance (NMR) spectroscopic and mass spectrometric analyses. Its absolute configuration was established by combining NMR quantum chemical calculations and comparison between the experimental and calculated circular dichroism (CD) curves. Additionally, the antibacterial assay of compound 1 was performed. As a result, compound 1 showed in vitro anti-Mycobacterium tuberculosis with MIC value of 32 µg/mL, together with moderate antibacterial activity against Staphylococcus aureus (MIC values = 64 µg/mL), and exhibited feeble activity against gram-positive Bacillus subtilis and gram-negative pathogen Escherichia coli (both MICs = 128 µg/mL).

Three New 2,2'-Difurylketone Derivatives and Two New Chromones from the Rehmanniae Radix Praeparata.

Rehmanniae Radix Praeparata is the processed products of the root of Rehmannia glutinosa. It has been used as a Traditional Chinese Medicine for thousands of years, and it has been found to possess widely pharmacological activities. In this study, three new 2,2'-difurylketone derivatives (rehmanniaeketone A-C) and two new chromones [3,8-dihydroxy-2-(2-hydroxyethyl)chromone and 3,8-dihydroxy-2-[(2-O-α-D-galactopyranosyloxy)ethyl]chromone] were isolated from the Rehmanniae Radix Praeparata. Furthermore all of the compounds were subjected to cytotoxic testing against the human lung carcinoma A549 cells. The cytotoxic results showed that rehmanniaeketone B and rehmanniaeketone C exhibited more stronger inhibition effects on the cell activity of A549 cells with the IC50 5.23 µM and 2.05 µM than other compounds. And 3,8-dihydroxy-2-(2-hydroxyethyl)chromone exhibited moderately inhibitory activity with the IC50 61 µM. Rehmanniaeketone A and 3,8-dihydroxy-2-[(2-O-α-D-galactopyranosyloxy]chromone showed no inhibitory effects.

Separation of three chromones from Saposhnikovia divaricata using macroporous resins followed by preparative high-performance liquid chromatography.

Prim-O-glucosylcimifugin, cimifugin, and 5-O-methylvisamminoside are three major chromone derivatives of Saposhnikovia divaricata that have many pharmacological activities, such as anti-inflammatory and antitumor activities. In the present work, an effective method for the simultaneous separation of prim-O-glucosylcimifugin, cimifugin, and 5-O-methylvisamminoside with high purities was established using HPD-300 resin coupled with preparative high-performance liquid chromatography. The adsorption kinetics curves of the three compounds on the HPD-300 resin were studied and found to fit well according to the pseudo-second-order equation. The adsorption isotherm results indicated that the adsorption process of the three compounds was exothermic. After a one-run treatment with the resin, the contents of prim-O-glucosylcimifugin, cimifugin, and 5-O-methylvisamminoside increased from 0.29, 0.06, and 0.37% to 13.07, 2.83, and 16.91% with recovery yields of 76.38, 78.25, and 76.73%, respectively. Finally, the purities of the three compounds were found to reach more than 95% after further separation using preparative high-performance liquid chromatography. The method developed in this study was effective and could simultaneously separate three chromones from Saposhnikovia divaricate. The experimental results also showed that the HPD-300 resin is suitable for the separation of chromone derivatives.

Anti-tyrosinase activity of South African Aloe species and isolated compounds plicataloside and aloesin.

Tyrosinase is the key enzyme in the production of melanin. Tyrosinase inhibitors have gained interest in the cosmetics industry to prevent hyperpigmentation and skin-related disorders by inhibiting melanin production. It has been reported that several Aloe species exhibit anti-tyrosinase efficacy in vitro. In this study, the exudates of thirty-nine South African Aloe species were screened to identify species and compounds with anti-tyrosinase activity. Qualitative screening revealed that twenty-nine Aloe species exhibited tyrosinase inhibition activity with one to three active bands. Quantitative screening was performed for 29 species and expressed as IC50 values. Three species were further analysed and subsequently, aloesin and aloeresin A was isolated from A. ferox and plicataloside from A. plicatilis and A. chabaudii. Aloeresin A was determined to be a substrate of mushroom tyrosinase. Dose-response assays showed that aloesin (IC50 = 31.5 µM) and plicataloside (IC50 = 84.1 µM) exhibited moderate to weak activity. Molecular docking scores for plicataloside were considerably lower than for aloesin (P < 0.01), confirming its lower IC50. Several Aloe species may have potential for the management of hyperpigmentation or as a skin lightening agent. This is the first report showing that plicataloside, present in A. plicatilis and A. chabaudii, exhibits anti-tyrosinase activity.

Two chromones with antimicrobial activity from the leaf latex of Aloe monticola Reynolds.

Aloesin (1) and 7-O-methyl-6'-O-coumaroylaloesin (2) were isolated from the leaf latex of Aloe monticola Reynolds, and their structures determined on the basis of NMR and mass spectroscopic analyses. The antimicrobial activities of the isolated chromones were evaluated against 21 bacterial and 4 fungal strains. Both compounds displayed antibacterial and antifungal effects against most bacterial and fungal strains tested, but their action was more prominent against Salmonella typhi, Shigella dysentery and Staphylococcus aureus (MIC = 10 µg/ml). Acute toxicity tests on mice revealed that neither the latex nor the isolated compounds possess toxicity up to a dose of 2000 mg/kg, signifying an oral LD50 greater than 2000 mg/kg. The results indicate that A. monticola possesses genuine in vitro antimicrobial effect attributed in full or in part to the presence of the isolated chromones in the latex.

Chromanones and aryl glucoside analogs from the entomopathogenic fungus Aschersonia confluens BCC53152.

Six new compounds [ascherlactones A (1) and B (2), ascherchromanone A (3), phenethyl 4'-O-methylglucoside (8), 4'-O-methylpleoside (10), and 4'-O-methyltorachrysone 8-O-glucoside (11)] and one naturally new compound [4'-O-methyl-ß-d-benzylglucoside (9)] together with fourteen known compounds, including paecilodepsipeptides A (5), B (7), and D (4), conoideocrellide A (6), eugenin (12), 5-hydroxy-2,3-dimethyl-7-methoxychromone (13), (S)-1-phenyl-1,2-ethanediol (14), (2S)-l-3-phenyllactic acid (15), papuline [or (2S)-l-3-phenyllactic acid methyl ester, 16], 2'-epi terpendole A (17), terpendoles C (18) and D (19), cholic acid, and zeorin were isolated from the entomopathogenic fungus Aschersonia confluens BCC53152. Their chemical structures were elucidated on the basis of NMR spectroscopic and mass spectrometric analyses. The absolute configurations were determined by using the evidence from NOESY correlations, chemical means, optical rotation values together with comparison of ECD spectroscopic data with the calculated ECD spectra. The plausible biosynthetic pathway of compounds 1-3 was also proposed. Moreover, antimicrobial activity such as antimalarial, antitubercular, antifungal, and antibacterial activities and cytotoxicity against cancerous (MCF-7, KB, and NCI-H187) and non-cancerous (Vero) cells of the isolated compounds were evaluated.

Five new 2-(2-phenylethyl)chromone derivatives from agarwood.

Agarwood has been used as an incense and in traditional medicines as aphrodisiac, sedative, cardiotonic, and carminative. In this study, five new 2-(2-phenylethyl)chromones (2, 13-16) and eleven known compounds (1, 3-12) were isolated from the agarwood. The structures of the new compounds were determined by 1H-, 13C-, and two-dimensional NMR together with electronic circular dichroism (ECD) spectroscopy. All isolated compounds were evaluated for the phosphodiesterase (PDE) 3A and 5A1 inhibitory activity by the fluorescence polarization method. Dimeric 2-(2-phenylehyl)chromones (13, 14, 16) had potent inhibitory activity to PDE 5A1 with IC50 values of micro molar range (13: 4.2 µM, 14: 7.9 µM, 16: 4.3 µM), whereas they had weak activity to PDE 3A. In contrast, compound (15), which has a phenylpropionic acid moiety instead of the 2-(2-phenylethyl)chromone moiety in the dimers, showed moderate inhibition of both PDE 3A (IC50: 42.6 µM) and PDE 5A1 (IC50: 15.1 µM).

Chromones and coumarins from Saposhnikovia divaricata (Turcz.) Schischk. Growing in Buryatia and Mongolia and their cytotoxicity.

ETHNOPHARMACOLOGICAL RELEVANCE: Saposhnikovia divaricata (family Apiaceae) a traditional medicinal plant distributed in many provinces of China, is well known for the pharmaceutical value and has been used for rheumatic arthritis, and anxiety in children. Antiviral, antioxidant and antiproliferative activities were also mentioned. The application of this plant are recorded in the Chinese Medicine (CM) classical text the Shen Nong's Materia Medica (Shen Nong Ben Cao Jing). In this monograph S. divaricata (syn Radix Ledebouriella divaricata) is graded as a premium-grade herb, with their broad-spectrum of therapeutic applications for the treatment of cough, common cold, arthralgia, as well as in rheumatic disorders. AIM OF THE STUDY: To isolate and identify chemical constituents (chromones and coumarins) from S. divaricata, collected in Buryatia and Mongolia and to study their in vitro anticancer activity against MEL-8, U-937, DU-145, MDA-MB-231 and ВТ-474 cell lines. MATERIALS AND METHODS: An 40% aqueous ethanol extract of the roots of S. divaricata was prepared and further successively fractionated by extraction with petroleum ether, diethyl ether, tert-butyl methyl ether and ethyl acetate. The obtained extracts were subjected to a series of chromatographic separations on silica gel for isolation of individual compounds. Isolated compounds were tested for their cytotoxicity with respect to model cancer cell lines using the conventional MTT assays. RESULTS: Total of 15 individual compounds: coumarins scopoletin 2, bergapten 3, isoimperatorin 4, marmesin 5, (+)-decursinol 9, (-)-praeruptorin B 10, oxypeucedanin hydrate 11, chromones: hamaudol 6, cimifugin 7, 5-О-methylvisamminol 8, chromone glycosides: prim-O-glucosylcimifugin 12, sec-O-glucosylhamaudol 13, 4'-O-ß-D-glucopyranosyl-5-О-methylvisamminol 14, 4'-O-ß-D-glucopyranosylvisamminol (15) and also polyyne compound panaxinol 1 were isolated and characterized. The structure of dihydropyranocoumarin 10 was confirmed by X-ray diffraction analyses. HPLC-UV method was used for determination of the content of most abundant chromones 7, 12 and 14 in the roots of S. divaricata, collected in Mongolia. Compounds 3-11 and 13, 14 were evaluated for their cytotoxicity with respect to model cancer cell lines. All the compounds were non-toxic in the hemolysis test. CONCLUSION: This report about the phytochemical profiles of S. divaricata growing in Mongolia and Buryatia led to the identification of 14 compounds including coumarins and chromones. The available coumarins and chromones may serve as new leads for the discovery of anticancer drugs.

Matteucinol, isolated from Miconia chamissois, induces apoptosis in human glioblastoma lines via the intrinsic pathway and inhibits angiogenesis and tumor growth in vivo.

Gliomas account for nearly 70% of the central nervous system tumors and present a median survival of approximately 12-17 months. Studies have shown that administration of novel natural antineoplastic agents is been highly effective for treating gliomas. This study was conducted to investigate the antitumor potential (in vitro and in vivo) of Miconia chamissois Naudin for treating glioblastomas. We investigated the cytotoxicity of the chloroform partition and its sub-fraction in glioblastoma cell lines (GAMG and U251MG) and one normal cell line of astrocytes. The fraction showed cytotoxicity and was selective for tumor cells. Characterization of this fraction revealed a single compound, Matteucinol, which was first identified in the species M. chamissois. Matteucinol promoted cell death via intrinsic apoptosis in the adult glioblastoma lines. In addition, Matteucinol significantly reduced the migration, invasion, and clonogenicity of the tumor cells. Notably, it also reduced tumor growth and angiogenesis in vivo. Moreover, this agent showed synergistic effects with temozolomide, a chemotherapeutic agent commonly used in clinical practice. Our study demonstrates that Matteucinol from M chamissois is a promising compound for the treatment of glioblastomas and may be used along with the existing chemotherapeutic agents for more effective treatment.

Antimicrobial secondary metabolites of an endolichenic Aspergillus niger isolated from lichen thallus of Parmotrema ravum.

A new 6-benzyl-γ-pyrone (1), named aspergyllone was isolated from the culture filtrates of an endolichenic fungus Aspergillus niger Tiegh, obtained from lichen thallus Parmotrema ravum (Krog & Swinscow) Serus, collected in India. 1 was isolated for the first time from an endolichenic fungus together with six other known metabolites identified as aurasperones A (2) and D (3), asperpyrone A (4), fonsecinone A (5), carbonarone A (6) and pyrophen (7). The compounds were tested against a panel of human, plant, food borne and fish pathogens. Aspergyllone showed strong selective antifungal activity against Candida parapsilosis (Ashford) Langeron & Talice, with an IC50 of 52 µg/mL. Aurasperone A and pyrophen showed moderate to strong antimicrobial activity inhibiting seven different test pathogens, being pyrophen active with IC50 ranging from 35 to 97 µg/mL.[Formula: see text].

Anti-inflammatory effects of mulberry (Morus alba L.) root bark and its active compounds.

Mulberry (Morus alba L.) root bark (MRB) was extracted using methanol and the extracts were subjected to tests of anti-inflammatory effects. The ethyl acetate fraction demonstrated the best anti-inflammatory effects. Purified compounds, sanggenon B, albanol B and sanggenon D, showed inhibitory effects on NO production in LPS-stimulated RAW264.7 cells and albanol B demonstrated the best anti-inflammatory effects. Regarding the underlying molecular mechanisms, further investigations showed that treatments with Albanol B reduced production of pro-inflammatory cytokines and decreased expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). These results would contribute to development of novel anti-inflammatory drugs from MRB.

Three new prenyloxy chromanones from aerial parts of Hypericum aucheri.

Three new prenyloxy chromanone derivatives, aucherine A-C (6, 7 and 9) as well as six known prenylated phloroglucinols (1-5 and 8) were isolated from the aerial parts of Hypericum aucheri Jaub. Et Spach. The structures of the isolated compounds were established by means of spectral techniques (HRESIMS, 1D and 2D NMR). The new compounds were tested on а panel of human tumor cell line using MTT assay. All tested compounds exerted moderate cytotoxicity with IC50 values ranging from 19.6 to 57.8 µM. The influence of the new compounds on some key signaling molecules (procaspase-9 and Bcl-xL), implicated in the regulation of programmed cell death was assessed by Western blot analysis.

Five new epoxy-5,6,7,8-tetrahydro-2-(2-phenylethyl)chromones from Chinese agarwood by artificial holing.

Five optically active epoxy-5,6,7,8-tetrahydro-2-(2-phenylethyl)chromone derivatives (1-5) with four chirality centers in the condensed cyclohexene ring were isolated from artificial holing agarwood originating from Aquilaria sinensis (Lour.) Gilg. Their structures were elucidated by spectroscopic techniques (UV, IR, 1D and 2D NMR) and MS analyses. The absolute configuration of 2 was elucidated by TDDFT-ECD calculations and ECD spectra of 1, 3-5 allowed their configurational assignment as well. All of the new compounds contained a condensed oxirane ring, and compound 1 was the only 6,7-epoxy-2-(2-phenylethyl)-5,6,7,8-tetrahydrochromone derivative that has ever been found in agarwood. AChE inhibitory activity was tested for the first time of these new compounds by using modified Ellman's colorimetric method. Compounds 3 and 5 exhibited inhibitory activity against AChE with IC50 value of 441.6, and 155.6 µM, respectively.

Asperpyrone F, a new dimeric naphtho-γ-pyrone from the edible fungus Pleurotus ostreatus.

A new dimeric naphtho-γ-pyrone, asperpyrone F (1), along with six known ones, asperpyrones B (2) and C (3), fonsecinones A (4) and B (5), aurasperones A (6) and E (7), have been isolated from the solid culture of the edible fungus Pleurotus ostreatus. The structures of 1-7 were determined mainly by NMR and MS experiments. The absolute configuration of compound 1 was assigned via the circular dichroism (CD) data analysis. Compounds 1-7 showed modest antioxidant and immunomodulatory activities. All compounds were isolated from the fungus P. ostreatus for the first time.

LC-MS-guided isolation of anti-inflammatory 2-(2-phenylethyl)chromone dimers from Chinese agarwood (Aquilaria sinensis).

Fifteen previously undescribed 2-(2-phenylethyl)chromone dimers, along with two known analogues were isolated from Chinese agarwood (Aquilaria sinensis) by a LC-MS-guided fractionation procedure. Their structures were elucidated on the basis of spectroscopic and spectrometric data (1D and 2D NMR, IR, and HRESIMS). The isolated compounds exhibited significant inhibition of nitric oxide production in lipopolysaccharide-stimulated RAW264.7 cells with IC50 values in the range 0.6-37.1 µM.

Rapid identification of antimicrometastases drugs using integrated model systems with two dimensional monolayer, three dimensional spheroids, and zebrafish xenotransplantation tumors.

Treating systemic metastases at the micrometastatic stage is a potential strategy to inhibit cancer metastasis. This study aims to establish an apoptosis sensor-based platform for rapid, effective, and noninvasive identification of drugs that can inhibit the proliferation of micrometastatic cancer cells. We stably transfected the plasmid DNA encoding the fluorescence resonance energy transfer-based caspase-3 sensor into highly metastatic melanoma B16F10 cells. The resulting B16F10-C3 cells were applied for screening of antiproliferative and proapoptotic drugs in two-dimensional (2D) monolayer, three-dimensional (3D) spheroids, and zebrafish xenotransplantation tumors. All studies were conducted in 96-well plates in a high throughput manner. Fourteen compounds including six chemotherapeutic drugs and eight kinase inhibitors were tested. Thirteen compounds failed the tests due to: Drug resistance, low efficacy, poor pharmacokinetic profile, and/or high side effects to zebrafish. The only compound that passed all tests was pan-phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, which inhibited the proliferation of B16F10-C3 cells in both 2D and 3D cultures. More important, it significantly reduced the xenograft tumor size in zebrafish by decreasing the viability of metastatic cancer cells. Our study suggests that the PI3K/AKT pathway is a potential therapeutic target for the reactivation of tumor dormancy and proliferation of micrometastases. Moreover, this integrated approach is effective for rapid identification of systemic antimetastases drugs.

Two New Chromone Glycosides from the Roots of Saposhnikovia divaricata.

Five chromone glycosides were isolated from the water-soluble portions of 70% EtOH extract of the roots of Saposhnikovia divaricata, including two new chromone glycosides 1 and 2. The structures of the chromone glycosides were identified as (3'S)-3'-O-ß-d-apiofuranosyl-(1 → 6)-ß-d-glucopyranosylhamaudol (1), (2'S)-4'-O-ß-d-apiofuranosyl-(1 → 6)-ß-d-glucopyranosylvisamminol (2), 3'-O-glucopyranosylhamaudol (3), 4'-O-ß-d-glucopyranosylvisamminol (4), and 4'-O-ß-d-glucopyranosyl-5-O-methylvisamminol (5) on the basis of extensive spectroscopic methods, and the absolute configurations of the new compounds were elucidated by the electronic circular dichroism (ECD) calculation and acid hydrolysis. The cytotoxic activities of the glycosides 1 - 5 against three human cancer cell lines (PC-3, SK-OV-3, and H460) were evaluated. The result showed that compounds 1 - 5 had weak cytotoxic activities against the human cancer cell lines with IC50 values in the range of 48.54 ± 0.80 - 94.25 ± 1.45 µm.

Isolation and identification of three new chromones from the leaves of Pimenta dioica with cytotoxic, oestrogenic and anti-oestrogenic effects.

CONTEXT: Pimenta dioica (L.) Merr. (Myrtaceae) is used in Costa Rican traditional medicine for women's health. Our previous work showed that P. dioica extracts were oestrogenic. OBJECTIVES: This work identifies phytochemicals from P. dioica that are responsible for the plant's oestrogen-like activities. MATERIALS AND METHODS: P. dioica leaves were collected in Costa Rica in 2005. Fractions resulting from chromatographic separation of a methanol extract were tested at 50 µg/mL in a competitive oestrogen receptor-binding assay. Active compounds were isolated by HPLC and identified by NMR and MS. Pure compounds were tested at 1 µM in the oestrogen-responsive SEAP reporter gene assay. The effects on cell viability, cytotoxicity and apoptosis were investigated in breast cancer (MCF-7 and SK-BR3) and gastric cancer (AGS and NCI-N87) cell lines using the ApoTox-Glo and Caspase-Glo assays and qPCR. RESULTS: Quercitrin and three new chromones, including a 2-phenoxychromone, 6,8-di-C-methylcapillarisin (1) were isolated and identified. Compound 1 caused a 6.2-fold increase in SEAP expression at 1 µM (p < 0.05). This activity was blocked by the ER antagonist ICI 182,780. Compound 2 caused a 6.0-fold increase in SEAP, inhibited the growth of MCF-7, AGS and NCI-N87 cells (IC50 54.27, 38.13 and 51.22 µg/mL, respectively), and induced apoptosis via caspase 8 and increased the Bax/Bcl-2 mRNA ratio in MCF-7 cells. Compound 3 was anti-oestrogenic in MCF-7 cells. DISCUSSION AND CONCLUSIONS: Compounds from P. dioica have oestrogenic, anti-oestrogenic and cytotoxic effects that may explain the ethnomedical use of this plant.

Antinociceptive activity of Inula britannica L. and patuletin: In vivo and possible mechanisms studies.

ETHNOPHARMACOLOGICAL RELEVANCE: Inula britannica L. is a predominant medicinal plant traditionally utilized in the treatments of arthritis and back pain in Iranian folk medicine. AIM OF THE STUDY: The purpose of this research was to evaluate the antinociceptive effects of Inula britannica L. flower essential oil (IBLEO) and one of its major constituents, Patuletin (Pn), in male mice. MATERIALS AND METHODS: In this study, we used pain assessment tests including acetic acid-induced writhing, tail-flick (TF), formalin induced paw licking (FIPL) model, and glutamate-induced paw licking (GPL). For understanding the supposed antinociceptive mechanisms of IBLEO, opioid and L-arginine/NO/cGMP/ KATP pathways were examined. RESULTS: In the TF, writhing, GPL, and FIPL tests, a dosage of 100 mg/kg of IBLEO showed noteworthy antinociceptive effects in comparison with control (p < 0.05). In writhing test, administration of selective opioid antagonists (naltrindole, nor-binaltorphimine, and naloxonazine) attenuated the antinociceptive effect of IBLEO in comparison with control (p < 0.001). Both methylene blue and glibenclamide blocked the antinociceptive effect of IBLEO (p < 0.05), but the administration of L-arginine or sodium nitroprusside fundamentally potentiated the antinociception induced by IBLEO in phase II of the FIPL (p < 0.05). Additionally, patuletin showed significant antinociceptive effects in writhing, FIPL, and GPL tests (p < 0.01). CONCLUSION: The results of this examination showed that IBLEO and Pn have antinociceptive effects. The modulation of glutamatergic systems by opioid receptors could be involved, at least in part, in these effects. Our data also suggest the activation of the L-arginine/NO/cGMP/KATP pathway in IBLEO antinociceptive effects.