Oxepine-containing pyrazinopyrimidine alkaloids and quinolinone derivatives produced by Aspergillus versicolor AS-212, a deep-sea-derived endozoic fungus.

Four new oxepine-containing pyrazinopyrimidine alkaloids, versicoxepines A - D (1-4), two quinolinone alkaloid analogs including 3-hydroxy-6-methoxy-4-phenylquinolin-2(1H)-one (5) and 3-methoxy-6-hydroxy-4-phenylquinolin-2(1H)-one (6) which were new naturally occurring compounds, together with two known compounds (7 and 8) were isolated from Aspergillus versicolor AS-212, an endozoic fungus isolated from the deep-sea coral Hemicorallium cf. imperiale, which was collected from the Magellan Seamounts in the Western Pacific Ocean. Their structures were determined by extensive analysis of the spectroscopic and X-ray crystallographic data as well as by chiral HPLC analysis, ECD calculation, and DP4+ probability prediction. Structurally, versicoxepines B and C (2 and 3) represent the first example of a new oxepine-containing pyrazinopyrimidine alkaloid whose cyclic dipeptide moiety is composed of the same type of amino acid (Val or Ile). Compound 5 displayed antibacterial activity against aquatic pathogens, Vibrio harveyi and V. alginolyticus, with MICs of 8 µg/mL.

New limonoids and quinolone alkaloids with cytotoxic and anti-platelet aggregation activities from Evodia rutaecarpa (Juss.) Benth.

One new limonoid, named 19-hydroxy methyl isoobacunoate diosphenol (1); one new degraded limonoid, named 9α-methoxyl dictamdiol (9); two new quinolone alkaloids, 1-methyl-3-[(7E,9E,12Z)-7,9,12-pentadecadienyl]-4(1H)-quinolone (11) and 1-methyl-3-[(7E,9E,11E)-7,9,11-pentadecadienyl]-4(1H)-quinolone (12), along with eight known compounds, evodol (2), 7ß-acetoxy-5-epilimonin (3), rutaevine (4), 6ß-acetoxy-5-epilimonin (5), limonin (6), obacunone (7), clauemargine L (8), hiiranlactone E (10) were isolated from the fruits of Evodia rutaecarpa (Juss.) Benth.. Structures of the four new compounds were elucidated on the basis of extensive spectroscopic techniques, including 1D and 2D NMR techniques. Compounds 3, 5, 9, 11 and 12 showed obviously cytotoxic activity against six human tumor lines, while compounds 11, 12 displayed anti-platelet aggregation induced by ADP at 50 µM and 100 µM.

Pyrroloquinolone A, a new alkaloid and other phytochemicals from Atractylis cancellata L. with antioxidant and anticholinesterase activities.

A new alkaloid pyrroloquinolone A (1), along with fifteen known compounds 2-16 were isolated from the petroleum ether, EtOAc and n-BuOH extracts of the whole plant Atractylis cancellata L. Their structures were elucidated on the basis of extensive spectroscopic analysis including 1D- and 2D-NMR and HR-ESI-MS techniques. This is the first report of alkaloids in the genus Atractylis. Some of the isolated compounds and extracts were evaluated for their antioxidant potential (scavenging activity of DPPH and ABTS radicals, and reducing Fe+3 and Cu+2 power assays) and acetylcholinesterase and butyrylcholinesterase inhibitory activities. Compounds 8 and 11 showed good antioxidant capacity compared to ascorbic acid, BHA, and BHT used as standards, whereas compounds 1 and 2 exhibited good anticholinesterase activities compared to galantamine used as standard.

Alkaloids from the nearly ripe fruits of Evodia rutaecarpa and their bioactivities.

Two novel quinolone alkaloids (1 and 2) and two novel indole alkaloids (5 and 8), together with eleven known analogues, were isolated from the nearly ripe fruits of Evodia rutaecarpa. Their structures were determined by extensive spectroscopic data, including NMR, HRESIMS, and ECD. Additionally, the anti-tumor, hypoglycemic, and anti-bacterial activities of the isolated alkaloids were evaluated in vitro. Compound 5 as a new alkaloid displayed moderate inhibitory effect against four human cancer cell lines (MCF-7 IC50 = 30.7 µM, Hepg-2 IC50 = 65.2 µM, A549 IC50 = 39.1 µM, and SHSY-5Y IC50 = 24.7 µM), α-glucosidase (IC50 = 23.9 µM) and PTP1B (IC50 = 75.8 µM). Compound 11 showed better inhibitory effect against PTP1B (IC50 = 16.2 µM) compared with that of the positive control. Compounds 5, 13, and 14 showed moderate inhibitory effects against Bacillus cereus with MIC values of 50, 25, and 10 µM, respectively.

Two new quinolone alkaloids from the nearly ripe fruits of Tetradium ruticarpum.

Tetradium ruticarpum (Juss.) Benth. belong to the family of Rutaceae. The complete and nearly ripe fruits of T. ruticarpum is used as traditional Chinese medicine and phytochemical investigations have been conducted on extracts of the seeds of T. ruticarpum to provide scientific validation of its properties. In this study, we successfully isolated two new quinolone alkaloids (1-2) from the MeOH extractive of nearly ripe fruits of T. ruticarpum. The structure elucidation of these compounds was determined by one- and two-dimensional nuclear magnetic resonance, ultraviolet and electrospray ionisation time-of-flight mass spectrometry. This finding expands the understanding of the natural constituents of the Rutaceae, in particular, the Tetradium genera.

Induction of Secondary Metabolites from the Marine-Derived Fungus Aspergillus versicolor through Co-cultivation with Bacillus subtilis.

A new cyclic pentapeptide, cotteslosin C (1: ), a new aflaquinolone, 22-epi-aflaquinolone B (3: ), and two new anthraquinones (9: and 10: ), along with thirty known compounds (2, 4:  - 8, 11:  - 34: ) were isolated from a co-culture of the sponge-associated fungus Aspergillus versicolor with Bacillus subtilis. The new metabolites were only detected in the co-culture extract, but not when the fungus was grown under axenic conditions. Furthermore, the co-culture extract exhibited an enhanced accumulation of the known constituents versicolorin B (14: ), averufin (16: ), and sterigmatocyctin (19: ) by factors of 1.5, 2.0, and 4.7, respectively, compared to the axenic fungal culture. The structures of the isolated compounds were elucidated on the basis of 1D and 2D NMR spectra and mass spectrometry as well as by comparison with literature data. The absolute configuration of compounds 3, 9: , and 10: was determined by ECD (electronic circular dichroism) analysis aided by TDDFT-ECD (time-dependent density functional theory electronic circular dichroism) calculations. Compounds 15, 18:  - 21: , and 26: exhibited strong to moderate cytotoxic activity against the mouse lymphoma cell line L5178Y, with IC50 values ranging from 2.0 to 21.2 µM, while compounds 14, 16, 31, 32: , and 33: displayed moderate inhibitory activities against several gram-positive bacteria, with MIC values ranging from 12.5 to 50 µM.

Identification of 4-phenylquinolin-2(1H)-one as a specific allosteric inhibitor of Akt.

Akt plays a major role in tumorigenesis and the development of specific Akt inhibitors as effective cancer therapeutics has been challenging. Here, we report the identification of a highly specific allosteric inhibitor of Akt through a FRET-based high-throughput screening, and characterization of its inhibitory mechanism. Out of 373,868 compounds screened, 4-phenylquinolin-2(1H)-one specifically decreased Akt phosphorylation at both T308 and S473, and inhibited Akt kinase activity (IC50 = 6 µM) and downstream signaling. 4-Phenylquinolin-2(1H)-one did not alter the activity of upstream kinases including PI3K, PDK1, and mTORC2 as well as closely related kinases that affect cell proliferation and survival such as SGK1, PKA, PKC, or ERK1/2. This compound inhibited the proliferation of cancer cells but displayed less toxicity compared to inhibitors of PI3K or mTOR. Kinase profiling efforts revealed that 4-phenylquinolin-2(1H)-one does not bind to the kinase active site of over 380 human kinases including Akt. However, 4-phenylquinolin-2(1H)-one interacted with the PH domain of Akt, apparently inducing a conformation that hinders S473 and T308 phosphorylation by mTORC2 and PDK1. In conclusion, we demonstrate that 4-phenylquinolin-2(1H)-one is an exquisitely selective Akt inhibitor with a distinctive molecular mechanism, and a promising lead compound for further optimization toward the development of novel cancer therapeutics.

A new isoquinolone alkaloid from an endophytic fungus R22 of Nerium indicum.

A new isoquinolone alkaloid named 5-hydroxy-8-methoxy-4-phenylisoquinolin-1(2H)-one (3), together with two known quinolinone alkaloids 3-O-methylviridicatin (1) and viridicatol (2) were isolated from the fermentation of an endophytic fungus Penicillium sp. R22 in Nerium indicum. Their structures were elucidated by NMR, IR and MS data, and were also confirmed by comparing with the reported data in the literature. Meanwhile, the antibacterial and antifungal activities of all compounds were tested, and the results showed that three compounds had strong antifungal activity. Among them, compound 2 revealed potent antibacterial activity against Staphylococcus aureus with MIC value of 15.6 µg/mL.

Melicodenine I, a new quinolinone alkaloid from Melicope denhamii leaves.

A new quinolinone alkaloid, Melicodenine I (1), along with five known compounds, bergapten (2), isoevodionol methyl ether (3), isoevodionol (4), ternatin (5), ß-sitosteryl-3-O-ß-D-glucopyranoside (6) and a mixture of ß-sitosterol and stigmasterol were isolated from Melicope denhamii leaves, and their structures were elucidated using 1H NMR, 13C NMR, 2D NMR and UPLC-qToF-MS.

Quinolone and indole alkaloids from the fruits of Euodia rutaecarpa and their cytotoxicity against two human cancer cell lines.

Four quinolone alkaloids (1-4) and three indole alkaloids (20-22), together with 30 known alkaloids (5-19, 23-37), were isolated from the fruits of Euodia rutaecarpa. Their structures were established by spectroscopic analyses. The in vitro cytotoxic activities of these alkaloids against leukaemia HL-60 and prostate cancer PC-3 cell lines were evaluated.

Inhibition of hepatitis C virus replication by chalepin and pseudane IX isolated from Ruta angustifolia leaves.

Hepatitis C virus (HCV) infection is highly prevalent among global populations, with an estimated number of infected patients being 170 million. Approximately 70-80% of patients acutely infected with HCV will progress to chronic liver disease, such as liver cirrhosis and hepatocellular carcinoma, which is a substantial cause of morbidity and mortality worldwide. New therapies for HCV infection have been developed, however, the therapeutic efficacies still need to be improved. Medicinal plants are promising sources for antivirals against HCV. A variety of plants have been tested and proven to be beneficial as antiviral drug candidates against HCV. In this study, we examined extracts, their subfractions and isolated compounds of Ruta angustifolia leaves for antiviral activities against HCV in cell culture. We isolated six compounds, chalepin, scopoletin, γ-fagarine, arborinine, kokusaginine and pseudane IX. Among them, chalepin and pseudane IX showed strong anti-HCV activities with 50% inhibitory concentration (IC50) of 1.7 ± 0.5 and 1.4 ± 0.2 µg/ml, respectively, without apparent cytotoxicity. Their anti-HCV activities were stronger than that of ribavirin (2.8 ± 0.4 µg/ml), which has been widely used for the treatment of HCV infection. Mode-of-action analyses revealed that chalepin and pseudane IX inhibited HCV at the post-entry step and decreased the levels of HCV RNA replication and viral protein synthesis. We also observed that arborinine, kokusaginine and γ-fagarine possessed moderate levels of anti-HCV activities with IC50 values being 6.4 ± 0.7, 6.4 ± 1.6 and 20.4 ± 0.4 µg/ml, respectively, whereas scopoletin did not exert significant anti-HCV activities at 30 µg/ml.

New isoquinolinequinone alkaloids from the South China Sea nudibranch Jorunna funebris and its possible sponge-prey Xestospongia sp.

Two new renieramycin-type bistetrahydroisoquinolinequinone alkaloids, fennebricins A (1) and B (5), and one new isoquinolinequinone alkaloid, N-formyl-1,2-dihydrorenierol (7), were isolated from the skin of the South China Sea nudibranch Jorunna funebris and its possible sponge-prey Xestospongia sp., together with eight known metabolites, including three bistetrahydroisoquinolinequinones (2-4) and five isoquinolinequinones (8-12). Their structures were elucidated by analysis of spectroscopic data including 1D and 2D NMR and high-resolution electrospray ionization mass spectrometry (HRESIMS) and by comparison with data for related known compounds. All the metabolites except for 7 occurred simultaneously in the two animals, supporting recent ecological studies that the nudibranch J. funebris preys on the sponge of the genus Xestospongia.

Vitiquinolone--a quinolone alkaloid from Hibiscus vitifolius Linn.

Phytochemical investigations of the powdered root of Hibiscus vitifolius Linn. (Malvaceae) was extracted successively with n-hexane and chloroform. Analysis of the n-hexane extract by GC-MS led to the identification of twenty-six components by comparison of their mass spectra with GC-MS library data. A novel quinolone alkaloid, vitiquinolone (5) together with eight known compounds viz. ß-Amyrin acetate (1), n-octacosanol (2), ß-Amyrin (3), stigmasterol (4), xanthyletin (6), alloxanthoxyletin (7), xanthoxyletin (8) and betulinic acid (9) were isolated from chloroform extract by column chromatography over silica gel. The structure of vitiquinolone was established on the basis of spectroscopic methods including UV, IR, 1D, 2D NMR and ESI-MS. The known compounds were identified on the basis of their physical and spectroscopic data as reported in the literature.

Sports doping: emerging designer and therapeutic ß2-agonists.

Beta2-adrenergic agonists, or ß2-agonists, are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptom-relievers and, in combination with inhaled corticosteroids, as disease-controllers. The use of ß2-agonists is prohibited in sports by the World Anti-Doping Agency (WADA) due to claimed anabolic effects, and also, is prohibited as growth promoters in cattle fattening in the European Union. This paper reviews the last seven-year (2006-2012) literature concerning the development of novel ß2-agonists molecules either by modifying the molecule of known ß2-agonists or by introducing moieties producing indole-, adamantyl- or phenyl urea derivatives. New emerging ß2-agonists molecules for future therapeutic use are also presented, intending to emphasize their potential use for doping purposes or as growth promoters in the near future.

Quinolone alkaloids with antibacterial and cytotoxic activities from the fruits of Evodia rutaecarpa.

Five new quinolone alkaloids, euocarpines A-E (16-20), four new natural products (1, 4, 12, and 14), and eleven known natural products were isolated from the fruits of Evodia rutaecarpa (Juss.) Benth. The structures of the new compounds were elucidated based on spectroscopic evidence. All compounds were evaluated for their antibacterial activity against three strains and for their cytotoxic activity against four human tumor cell lines. The results revealed that 5, 7-11, 13, 14, and 16-20 exhibited moderate antibacterial activities (MIC values: 4-128 µg/mL), and 9, 11, 14, and 17 exhibited moderate cytotoxic activities against HepG-2, Hela, BEL7402, and BEL7403 (IC50 values: 15.85-56.36 µM).

New cytotoxic quinolone alkaloids from fruits of Evodia rutaecarpa.

Three new quinolone alkaloids, 1-methyl-2-[7-hydroxy-(E)-9-tridecenyl]-4(1H)-quinolone (1), 1-methyl-2-[(Z)-4-nonenyl]-4(1H)-quinolone (2), 1-methyl-2-[(1E,5Z)-1,5-undecadienyl]-4(1H)-quinolone (3) and one new natural product, 1-methyl-2-[(E)-1-undecenyl]-4(1H)-quinolone (4), were isolated from the dried and nearly ripe fruits of Evodia rutaecarpa (Juss.) Benth., along with thirteen known compounds (5-17). In addition, one new artificial product, 1-methyl-2-[7-carbonyl-(E)-9-tridecenyl]-4(1H)-quinolone (1A) was also obtained. The structures of these compounds were determined by spectroscopic analyses. The cytotoxic activities of all of the compounds against the human cancer cell lines HL-60, N-87, H-460, and Hep G(2) cells were evaluated by MTT assay. The results showed that these alkaloids inhibited cell proliferation with IC(50) values between 14µM and 22µM.

A new quinolone and other constituents from the fruits of Tetradium ruticarpum: effects on neutrophil pro-inflammatory responses.

The fruit of Tetradium ruticarpum is widely used in healthcare products for the improvement of blood circulation, headache, abdominal pain, amenorrhea, chill limbs, migraine, and nausea. A new quinolone, 2-[(6Z,9Z)-pentadeca-6,9-dienyl]quinolin-4(1H)-one (1), has been isolated from the fruits of T. ruticarpum, together with eleven known compounds. The structure of the new compound was determined by NMR and MS analyses. Rutaecarpine (4), evodiamine (5), and skimmianine (7) exhibited inhibition (IC(50) < or = 20.9 microM) of O2(.-) generation by human neutrophils in response to N-formyl-L-methionyl-L-leucyl-L-phenylalanine/cytochalasin B (fMLP/CB). In addition, 1, evocarpine (2), 4, 7, and evodol (8) inhibited fMLP/CB-induced elastase release with IC(50) values < or =14.4 microM.

New pseudan (2-alkyl-4(1H)-quinolinone) alkaloids from Boronia ternata var. elongata and Boronia alulata (Rutaceae).

The aerial parts of Boronia ternata var. elongata from western Australia has yielded three new 2-acyl-4(1H)-quinolinone alkaloids, characterised as 2-n-pentyl-4(1H)-quinolinone, 1-methyl-2-n-pentyl-4(1H)-quinolinone and 1-methyl-2-(1 xi-methyl)-propyl-4(1H)-quinolinone, as well as known alkaloids of this class and a furoquinoline alkaloid. Boronia alulata, from northeast Queensland, also yielded 2-n-pentyl-4(1H)-quinolinone together with the known 2-n-propyl-4(1H)-quinolinone. Both species are assigned to Boronia section Valvatae which, alone among the sections of Boronia, appears to be characterised by the presence of alkaloids.

Isolation and identification of antifungal and antialgal alkaloids from Haplophyllum sieversii.

Bioassay-guided fractionation of the hexane/ethyl acetate/water (H/EtOAc/H2O) crude extract of the aerial parts of Haplophyllum sieversii was performed because of preliminary screening data that indicated the presence of growth inhibitory components against Colletotrichum fragariae, Colletotrichum gloeosporioides, and Colletotrichum acutatum. Fractionation was directed using bioautographical methods resulting in the isolation of the bioactive alkaloids flindersine, anhydroevoxine, haplamine, and a lignan eudesmin. These four compounds were evaluated for activity against C. fragariae, C. gloeosporioides, C. acutatum, Botrytis cinerea, Fusarium oxysporum, and Phomopsis obscurans in a dose-response growth-inhibitory bioassay at 50.0, 100.0, and 150.0 microM. Of the four compounds tested, flindersine demonstrated the highest level of antifungal activity. Additionally, flindersine, eudesmin, and haplamine were screened against the freshwater phytoplanktons Oscillatoria perornata, Oscillatoria agardhii, Selenastrum capricornutum, and Pseudanabaena sp. (strain LW397). Haplamine demonstrated selective inhibition against the odor-producing cyanobacterium O. perornata compared to the activity against the green alga S. capricornutum, with lowest observed effect concentration values of 1.0 and 10.0 microM, respectively.