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Bioassay-guided fractionation of Cladosporium cladosporioides (Fresen.) de Vries extracts led to the isolation of four compounds, including cladosporin, 1; isocladosporin, 2; 5'-hydroxyasperentin, 3; and cladosporin-8-methyl ether, 4. An additional compound, 5',6-diacetylcladosporin, 5, was synthesized by acetylation of compound 3. Compounds 1-5 were evaluated for antifungal activity against plant pathogens. Phomopsis viticola was the most sensitive fungus to the tested compounds. At 30 μM, compound 1 exhibited 92.7, 90.1, 95.4, and 79.9% growth inhibition against Colletotrichum acutatum , Colletotrichum fragariae , Colletotrichum gloeosporioides , and P. viticola, respectively. Compound 2 showed 50.4, 60.2, and 83.0% growth inhibition at 30 μM against Co. fragariae, Co. gloeosporioides, and P. viticola, respectively. Compounds 3 and 4 were isolated for the first time from Cl. cladosporioides. Moreover, the identification of essential structural features of the cladosporin nuclei has also been evaluated. These structures provide new templates for the potential treatment and management of plant diseases.

In this study, we examined in vitro antibacterial, antifungal, antimalarial, and antileishmanial activities of secondary metabolites (1-8) isolated from the fungus Eurotium repens. All compounds showed mild to moderate antibacterial or antifungal or both activities except 7. The activity of compound 6 was the best of the group tested. The in vitro antimalarial evaluation of these compounds revealed that compounds 1-3, 5, and 6 showed antimalarial activities against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum with IC(50) values in the range of 1.1-3.0 μg/ml without showing any cytotoxicity to the mammalian cells. Compound 5 displayed the highest antimalarial activity. Antileishmanial activity against Leishmania donovani promastigotes was observed for compounds 1-6 with IC(50) values ranging from 6.2 to 23 μg/ml. Antileishmanial activity of compounds 5 and 6 (IC(50) values of 7.5 and 6.2 μg/ml, respectively) was more potent than 1-4 (IC(50) values ranging from 19-23 μg/ml). Compounds 7 and 8 did not show any antiprotozoal effect. Preliminary structure and activity relationship studies indicated that antibacterial, antifungal, antimalarial, and antileishmanial activities associated with phenol derivates (1-6) seem to be dependent on the number of double bonds in the side chain, which would be important for lead optimization in the future.

In the first decade of the twenty-first century, the occurrence of cancers has increased not only in First World countries but also in those countries considered to have a lower standard of living, according to a world cancer report issued in 2008 for the IARC Nonserial Publication by Boyle and Levin. So widespread is cancer, in its various forms, that most adults have either had family members or had friends who have been afflicted by the disease. Projected figures for cancers indicate, in the aforementioned publication, that 12 million cancer cases were diagnosed in 2008 alone and that the number of cancer victims has doubled since 1978. Coupled to the psychological impact that a diagnosis has on an individual is the cost of treatment that must also be considered. Again, according to the National Cancer Institute (December 2008) these costs are estimated to be US$147 billion by 2020. An article, published in USA Today, claims that new cancer cases in 2008 were projected to be 40,480. And the cost for elderly Medicare patients will be US$21.1 billion for 5 years of treatment for the period 2004–2009. Sadly, one in eight patients with advanced stages of cancer will turn down the offer of recommended care because of costs. While cases may have been misdiagnosed in the twentieth century, the sophisticated techniques available today give a clearer graph of the incidence of the disease. With advanced diagnostics, there has been a concomitant advance in anticancer chemotherapy. Keywords: cancer; cytotoxic agents; DNA; therapeutic agents

A series of m-terphenyl amines was synthesized and evaluated as a novel class of cyclooxygenase (COX) inhibitors. Structure–activity relationships (SAR) were investigated by functional group modification at the para-position of the C-1′ and C-2′ phenyl substituents on the central aromatic ring. Anilines 6a, b, d, and h demonstrated nonselective inhibition of COX-1 and -2 in human whole blood. Compounds 6c and e demonstrated preferential inhibition of the COX-2 isozyme at 10 μM. Molecules 6f, i, and j inhibited only COX-1, and the disubstituted ethoxy derivative (6g) was inactive as a COX inhibitor (≤ 100 μM). Molecular docking studies of these compounds indicate that the COX-1 binding site amino acid Ile523 anchors the m-terphenyl system statically within the enzyme’s active site, while the slightly smaller amino acid Val523 in COX-2 allows the ligand to “roll,” fashioning several acceptable conformers.

Botcinins E and F were isolated together with the known botcinolide. The structures of botcinins E and F were determined to be 3-O-deacetylbotcinin A (5) and 3-O-deacetyl-2-epi-botcinin A (6), respectively, by spectroscopic methods and chemical conversion. The structure of botcinolide was revised on the basis of spectroscopic data and chemical conversion. Botcinolide was originally reported as a nine-membered lactone (7), but the revised structure is the seco acid of botcinin E (13). Thus botcinolide is renamed botcinic acid, and homobotcinolide is renamed botcineric acid. Reinvestigation of the spectroscopic data reported for all botcinolide analogues indicates that 4-O-methylbotcinolide and 3-O-acetyl-2-epibotcinolide are the same as a methyl ester of botcinic acid (13a) and botcinin A (1), respectively, and that 2-epibotcinolide may be the same as botcinin E (5). Compounds 5, 6, and 13 showed weak antifungal activity against Magnaporthe grisea, a pathogen of rice blast disease.

9-O-methylfusarubin was isolated from a novel source, Fusarion oxysporum, and evaluated for its phytotoxic and chlorotic inducing properties in plants as well as its potential as an antineoplastic agent. Etiolated wheat coleptiles were inhibited 100 and 40%, respectively, at 10-3 and 10-4 M. Bean plants were necrotic and chlorotic, with leaf malformations, following 10-2 M treatments. Corn plants were chlorotic following 10-3 and 10-4 M treatments. Tobacco plants exhibited subtle interveinal chlorosis with 10-2 M applications. All agrochemical effects were substantial, but transient. The anticancer properties were evaluated using ras transformed liver epithelial cells. Doses ranging from 12.5-50 μM provided a dose-dependent reduction in the number of viable cells when compared to controls. At the 50 μM dose, the number of viable cells was reduced by 65% suggesting potential antineoplastic effects of 9-O-methylfusarubin.

The cyanobacterium (blue-green alga) Oscillatoria perornata is the major cause of musty off-flavor in farm-raised channel catfish Ictalurus punctatus in western Mississippi. Currently, the only federally approved compounds for use as selective algicides in catfish aquaculture ponds in the southeastern United States are the herbicide diuron and copper-based products (e.g., copper sulfate). Due to environmental issues and the broad-spectrum toxicity of these synthetic algicides to nontarget organisms, there is a need for environmentally safe algicides for controlling O. perornata in catfish ponds. Laboratory bioassay screening of the natural product SeaKleen, a quinone-based biocide used to treat the ballast water from ships, found that it is selectively toxic towards O. perornata compared with the green alga Selenastrum capricornutum. Subsequently, efficacy testing of SeaKleen was performed using limnocorrals placed in catfish aquaculture ponds containing O. perornata blooms. Two studies were perf...

Innumerable toxic substances present in the environment inhibit gap junctions, intercellular membrane channels that play fundamental roles in coordinated function of cells and tissues. Included are persistent organochlorine compounds, which pose health risks to humans and animals owing to their widespread use, bioaccumulation, and ability to inhibit gap junction channel-mediated intercellular communication in liver, lung, skin, heart, and brain cells. In this study, the organochlorine xenobiotics dieldrin and endosulfan, at micromolar concentrations, were found to inhibit gap junction-mediated intercellular communication and induce hypophosphorylation of connexin 43 in cultured rat astrocytes, the predominant cell type in the brain coupled through gap junctions. This inhibition of gap junctional communication was substantially reduced by preincubation with chaetoglobosin K (ChK), a bioactive natural produce previously shown to have ras tumor suppressor activity. Chaetoglobosin K also prevented dieldrin and endosulfan-induced hypophosphorylation of connexin 43 and prevented dieldrin-induced connexin 43 plaque dissolution in both astrocytes and cultured liver epithelial cells. The results suggest that stabilization of the native, phosphorylated form of connexin 43 by ChK may contribute to its ability to prevent organochlorine-induced inhibition of gap junction-mediated communication and dissolution of gap junction plaques within the plasma membrane.

Four new metabolites with carotane skeletons, trichocaranes A (1), B (2), C (3), and D (4), were isolated from Trichoderma virens and their structures established by the interpretation of NMR and mass spectroscopic data. The trichocaranes significantly inhibited the growth of etiolated wheat coleoptiles: 40% at 10(-4) M with 1 and 2 and 86% at 10(-3) M with 3.

(+)-Brevione A, the first member of a novel family of bioactive spiroditerpenoids, a potential allelopathic agent, has been isolated from the ethyl acetate active fractions of the aqueous acetone extracts of semi-solid fermented Penicillium brevicompactum Dierckx. The structure displays the novel spiroditerpenoid skeleton of breviane. The structure elucidation of brevione A was performed by homo- and hetero-nuclear 2D NMR spectral data. On the basis of combined studies of the theoretical conformations and NOEDIFF data, its relative stereochemistry is proposed.

White grape seeds were subjected to sequential supercritical fluid extraction. By increasing the polarity of the supercritical fluid using methanol as a modifier of CO2, it was possible to fractionate the extracted compounds. Two fractions were obtained; the first, which was obtained with pure CO2, contained mainly fatty acids, aliphatic aldehydes, and sterols. The second fraction, obtained with methanol-modified CO2, had phenolic compounds, mainly catechin, epicatechin, and gallic acid. The fractions were bioassayed. Antimicrobial activities were checked on human pathogens, and a high degree of activity was obtained with the lipophilic fraction. Agrochemical activities on phytopathogenic fungi and activities on the etiolated wheat coleoptile bioassay were also checked. The more polar fraction was active in the latter bioassay. Keywords: Supercritical fluids; seeds; antimicrobial; extraction; grapes

The formation of 2,2-dinitrocyclopentanone oxime is described during an attempted nitroacetamidation of cyclopentenecarboxaldehyde using ceric ammonium nitrate and sodium nitrite in acetonitrile. Progress towards the total synthesis of 1-amino-2-nitrocyclopentanecarboxylic acid is also discussed.

Bioassay-guided fractionation of a fungus Neocosmospora sp. (UM-031509) resulted in the isolation of three new resorcylic acid lactones, neocosmosin A (2), neocosmosin B (3), and neocosmosin C (4). Three known resorcylic acid lactones, monocillin IV (1), monocillin II (5), and radicicol (6), were also isolated and identified. The structures of these compounds were established on the basis of extensive 1D and 2D NMR spectroscopic analysis, mass spectrometric (ESIMS) data, and X-ray crystallography. Compounds 4-6 show good binding affinity for the human opioid receptors. These findings have important implications for evaluating the potential psychoactive effects with this class of compounds.

Bioassay-directed fractionation of an extract from the fungus Nigrospora sphaerica (strain UK181RRC) yielded a new 14-membered lactone, named nigrosporolide, whose structure was established by spectroscopic techniques. This compound inhibited the growth of etiolated wheat coleoptiles.

Biologically active natural products of microbial origin are diverse in chemical structure and exhibit different responses in divergent assay systems. They may have practical use as plant growth regulators, antimicrobials, and phytotoxins. In addition, they may be viewed as bioactive templates that may be altered to produce compounds with changed specific activities and target specificities.

In addition to antafumicins A and B, and cytochalasin, the bioactive compounds expansolides A and B have been isolated from Aspergillus fumigatus Fresenius. Their absolute configuration has been established by using the modified Mosher's method. The bioactivity of all isolated compounds has been evaluated.

The structure of botcinolide, a new, phytotoxic, trihydroxlated nona-lactone, esterified with 4-hydroxy-2-octenoic acid, has been elucidated using both spectroscopic and chemical techniques. Botcinolide is a metabolite of the mould Botrytis cinerea (UK185RRC)

Bioassay-guided fractionation of the fungus Eurotium repens resulted in the isolation of two new benzyl derivatives, (E)-2-(hept-1-enyl)-3-(hydroxymethyl)-5-(3-methylbut-2-enyl)benzene-1,4-diol (1) and (E)-4-(hept-1-enyl)-7-(3-methylbut-2-enyl)-2,3-dihydrobenzofuran-2,5-diol (2), along with seven known compounds (3-9) including five benzaldehyde compounds, flavoglaucin (3), tetrahydroauroglaucin (4), dihydroauroglaucin (5), auroglaucin (6), and 2-(2',3-epoxy-1',3'- heptadienyl)-6-hydroxy-5-(3-methyl-2-butenyl)benzaldehyde (7), one diketopiperazine alkaloid, echinulin (8), and 5,7-dihydroxy-4-methylphthalide (9). The chemical structures of these compounds were established on the basis of extensive 1D and 2D NMR and HRMS data. Compounds 1-4 and 6 showed good binding affinity for human opioid or cannabinoid receptors. These findings have important implications for psychoactive studies with this class of compounds.

Extraction of the fungus Cladosporium cladosporioides yielded the known isocoumarin, cladosporin [1], and a new compound. This metabolite, which inhibited the growth of etiolated wheat coleoptiles slightly more than did cladosporin, was characterized as a diastereoisomer of cladosporin at C-14 and was named isocladosporin [2].

The fungal metabolite moniliformin and several small ring analogues were evaluated for potential substrate and inhibitory activity in the rat lens aldose reductase (AR) assay. Even though all of these compounds possess carbonyl moieties and structural similarities to AR substrates, none were found to function as substrates over a concentration range of 1.0 mM to 10 μM. All of the compounds did display inhibitory activity with IC50s ranging from 19–110 μM. The most inhibitory compounds were the four-membered ring moniliformin (ICI 19 μM), the five-membered analogue croconic acid (IC50 28 μM) and six-membered derivative tetrahydroxy p-benzoquinone (1C50 23 μM). Modification of moniliformin by methylation (methyl moniliformin) or hydroxylation (squaric acid) resulted in a significant decline in inhibitory activity. All of the compounds evaluated except moniliformin displayed uncompetitive, non-competitive or mixed-type kinetics relative to the substrate (glyceraldehyde) and cofactor (NADPH), kinetic ...

A new chroman derivative, named ruakuric acid, was isolated from a strain of Aspergillus fumigatus growing in conjunction with a coral lichen. The structure was determined as 6-acetyl-5-hydroxy-4-methoxy-chroman-2-carboxylic acid (mixture of 2,4-cis,trans isomers).

Fermentation of Nigrospora sphaerica on shredded wheat medium generated the novel metabolite, epoxyexserohilone, a congener of the known phytotoxin, exserohilone. Single crystal X-ray diffraction determined the structure and absolute stereochemistry of this metabolite which had the molecular formula C20H22N2O6S2, melting point 190–192°C, and an EI-MS identical with its congener exserohilone. The metabolite did not exhibit biological activity in an etiolated wheat coleoptile bioassay, neither was it active against Gram-positive or Gram-negative bacteria.

A new compound, euparvic acid (1, C(14)H(16)O(6)), and the known compounds 5,7-dihydroxy-4-methylphthalide (2), 6-(3-carboxybutyl)-7-hydroxy-5-methoxy-4-methylphthalan-1-one (3), 6-(5-carboxy-3-methylpent-2-enyl)-7-hydroxy-5-methoxy-4-methylphthalan-1-one (4), and 6-(5-carboxy-4-hydroxy-3-methylpent-2-enyl)-7-hydroxy-5-methoxy-4-methylphthalan-1-one (5) were isolated from the EtOAc extract of Eupenicillium parvum. The structure of 1 was determined by interpretation of MS and homo- and heteronuclear 2D NMR spectroscopic data and confirmed by X-ray crystallography. The absolute configuration of 5 was determined via MPA ester derivatization.

A new metabolite, koninginin G (1), was isolated from a strain of Trichoderma aureoviride and its structure established by the interpretation of spectroscopic data. The metabolite significantly inhibited the growth of etiolated wheat coleoptiles by 56% at 10(-3) M.

Purpose: Chaetoglobosin K (ChK), a bioactive natural product previously shown to have anti-tumor promoting activity in glial cells and growth inhibitory effects in ras-transformed fibroblasts, inhibited anchorage-dependent and anchorage-independent growth in ras-transformed liver epithelial cells. The purpose of this study was to identify cellular targets of ChK that mediate its anti-tumor effects. Methods: Anchorage-independent cell growth assays, using soft agar-coated dishes, and anchorage-dependent growth assays were performed on transformed WB- ras1 cells. Phase/contrast and fluorescent microscopy were used to visualize cell morphological changes and DAPI-stained nuclei. Analyses of p21 Ras membrane versus cytosolic forms, p44/42 mitogen-activated protein kinase (MAPK) phosphorylation, Akt kinase phosphorylation and connexin 43 phosphorylation were performed by Western blotting. Gap junction-mediated cellular communication was measured by fluorescent dye transfer. Results: Treatment of WB- ras1 cells with a non-cytotoxic dose of ChK inhibited both anchorage-dependent and anchorage-independent growth. Inhibited cells were generally larger and less spindle-shaped in morphology than vehicle-treated cells, many of which were multinucleate. Removal of ChK induced cytokinesis and a return to predominantly single-nucleate cells, suggesting that ChK inhibits cytokinesis. The proportion of membrane-associated versus cytosolic forms of p21 Ras was unchanged by ChK treatment, suggesting that ChK does not act as a farnesylation inhibitor. ChK treatment decreased the level of phosphorylation of Akt kinase, a key signal transducer of the Phosphatidylinositol 3-kinase pathway. In contrast, ChK had no effect on phosphorylation of p44/42 MAPK, which mediates the MAPK/ERK Ras effector pathway. Phosphorylation of the gap junction protein, connexin 43, shown previously to increase following treatment with other anti-Ras compounds, was also not altered by ChK, which correlated with its lack of effect on gap junction-mediated cellular communication. Conclusions: Our results demonstrate that ChK inhibits Akt kinase phosphorylation and cytokinesis in ras-transformed cells, which likely contribute to its ability to inhibit tumorigenic growth.

A novel natural product exhibiting biological activity was isolated from a strain of Botrytis cinerea that had infected raspberry fruit (Rubus ideaus). Liquid fermentation and bioassay-directed fractionation of the organism yielded a compound with molecular formula C22H38O8 that is trivially named homobotcinolide. It significantly inhibited etiolated wheat coleoptile growth. Greenhouse-grown bean, corn, and tobacco plants were also affected by exogenous application of homobotcinolide, severe chlorosis and necrosis being exhibited in corn. The compound is a polyhydroxylated nonalactone esterified with 4-hydroxy-2-decenoic acid.

The arrival of new plant growth regulators on the market in the early 1990s, especially synthetic ones, is in a static state. Many growth regulators continue to be used experimentally, but the transition to approved usage is being delayed for several reasons. On the financial side, a number of mergers, buy-outs, and other dispositions of chemical companies has led to a decrease in the number of commercial compounds available. Moreover, the cost of registration has prompted some producers to withdraw chemicals from the market. Some older plant growth regulators have undergone several trade name changes, adding confusion to the field. The ideal plant growth regulator should leave no harmful persistent residue in a finished product or crop and the paradigm compounds are ones that have high specific activity, are target specific, and are environmentally biodegradable. The most acceptable growth regulators appear to be those compounds that already occur in nature and elicit certain desirable responses in economic crops. Keywords: Natural products; Growth regulators; Brassinosteroids; Cytokinens; n-Decanol; Gbberllins; Ethylene; Dikegulac; Lactic acid; Natural products; derivatives; Synthetic products; Experimental products

Koninginin E, a congener of previously isolated Koninginins A, B, and C, was isolated from Trichoderma koningii fermented on a shredded wheat medium. Selective supercritical fluid extraction was used in the rapid isolation of this otherwise intractable compound. Koninginin E inhibited the growth of etiolated wheat coleoptiles by 65% at 10−3 M.

A novel biologically active natural product was isolated from a strain of Botrytis cinerea found on cultivated raspberry fruit (Rubus ideaus) upon fermentation in a liquid medium. Following a bioassay-directed purification process, the final product was an amorphous solid with the molecular formula C20H34O8, and is trivially named botcinolide. It significantly inhibited etiolated wheat coleoptile growth at 10−3 and 10−4 M by 100 and 82% respectively, relative to the controls. Greenhouse-grown bean, corn, and tobacco plants were affected by treating with botcinolide, and exhibited chlorosis and severe necrosis at 10−2 and 10−3 M. The structure is a new hydroxylated nonalactone that is esterified with 4-hydroxy-2-octenoic acid.

The structures of four new, naturally occurring bioactive spiroditerpenoids, (+)-breviones B, C, D, and E, potential allelopathic agents, have been determined from extracts of semisolid fermented Penicillium brevicompactum Dierckx. The structures display the novel breviane spiroditerpenoid skeleton. Structure elucidation was performed by chemical transformations and by homo- and heteronuclear 2D-NMR spectral data. On the basis of combined studies of the theoretical conformations and NOEDIFF data, their relative stereochemistry is proposed. A mixed biogenesis for this novel family of spiroditerpenoids is tendered. The levels of activity shown by breviones B, C, and E in the etiolated wheat coleoptiles bioassay, especially breviones E (100% inhibition) and C (80% inhibition) both at 10(-4) M, suggest them as lead compounds for new agrochemicals.

Much has been written in the field of agrochemicals about the application of phenoxy compounds as herbicidal agents. The illustrious history of these agents includes their accelerated development by the Allies for use during World War II. Among the most famous of these agents are 2,4-dichlorophenoxyacetic acid (2,4-D) and its congener, 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). Because of their high specific activities, these compounds became templates for the production of a number of plant growth regulators such as Fruitone and Tomato Bloom. Interestingly, the pharmaceutical industry was developing a group of phenoxy derivatives which proved to be useful in the treatment of type III hyperlipoprotenemia, a condition where triglycerides and total cholesterol levels are elevated. The most recognized agent in this pharmaceutical class is clofibrate which inhibits sn-glyceryl-3 phosphate acyltransferase, the enzyme responsible for the conversion of acetate to mevalonate. Furthermore, its mechanism of action also includes inhibition of 3-hydroxy-3-methylglutaryl-CoA (HMGCoA) reductase. In addition, the aftermath of World War II served as a catalyst in the development of the benzodiazepines, a well recognized pharmaceutical class possessing sedative/hypnotic and tranquilizing properties. It is of interest to note that these agents are actually allelopathic natural products whose chemical structures were ignored until the development of Valium as a pharmaceutical agent. Had these natural product chemical templates not been relegated to library book shelves, they may have served a useful purpose in their development as medicinals. Recently, some benzodiazepines have been shown to possess agrochemical properties including inhibition against Phytophthora infestans, late blight of potato. The separate, but distinct, agrochemical and pharmaceutical development of various classes of agents will be discussed.

(1991). Biological Activity of ( – )-Harziano-pyridone Isolated from Trichoderma harzianum. Agricultural and Biological Chemistry: Vol. 55, No. 10, pp. 2629-2631.