Vertilecanins: new phenopicolinic acid analogues from Verticillium lecanii.

Five new phenopicolinic acid analogues (1-5) have been isolated from solid-substrate fermentation cultures of Verticillium lecanii. The most abundant component (vertilecanin A; 1) displays antiinsectan activity against Helicoverpa zea. These compounds were obtained by chromatographic fractionation of the EtOAc culture extract and identified by analysis of NMR and MS data. The known fungal metabolites 2-decenedioic acid and 10-hydroxy-8-decenoic acid were also isolated from these cultures.

Bombardolides: new antifungal and antibacterial gamma-lactones from the coprophilous fungus Bombardioidea anartia.

Chemical studies of organic extracts from cultures of the coprophilous fungus Bombardioidea anartia have led to the discovery of bombardolides A--D (1--4), a series of new antifungal and antibacterial metabolites. Three of these metabolites (1--3) were obtained as inseparable pairs of geometric isomers. A new 3-substituted phenol (5) and the known compound asterriquinone B4 were also encountered. The structures of compounds 1--5 were determined by analysis of NMR and MS data.

Pseudodestruxins A and B: new cyclic depsipeptides from the coprophilous fungus Nigrosabulum globosum.

Pseudodestruxins A (1) and B (2), two new cyclic peptides, have been isolated from cultures of the coprophilous fungus Nigrosabulum globosum. The structure of pseudodestruxin A (1) was elucidated using 2D NMR techniques and confirmed by single-crystal X-ray diffraction analysis. The structure of 2 was assigned by comparing its NMR and FABMS data with those of compound 1. The known compounds ascochlorin and 5-chlorocollectorin B were also isolated from N. globosum. Although 1 and 2 display antibacterial effects, ascochlorin was found to be responsible for the antifungal activity of the crude extract.

New cyclic peptide and bisindolyl benzenoid metabolites from the sclerotia of Aspergillus sclerotiorum.

Scleramide (1), a new cyclic hexapeptide, and a new oxidized bisindolyl benzenoid derivative (2' '-oxoasterriquinol D methyl ether, 2) were isolated from extracts of the sclerotia of Aspergillus sclerotiorum (NRRL 5167). The structures of these compounds were determined by analysis of 1D and 2D NMR experiments.

Tenellic acids A-D: new bioactive diphenyl ether derivatives from the aquatic fungus Dendrospora tenella.

Tenellic acids A-D (1-4) were isolated from cultures of the freshwater fungus Dendrospora tenella. The structures of these new diphenyl ether derivatives were determined primarily by analysis of NMR data. Compounds 1-4 display antimicrobial activity against Gram-positive bacteria.

Sporovexins A-C and a new preussomerin analog: antibacterial and antifungal metabolites from the coprophilous fungus Sporormiella vexans.

Sporovexins A-C (1-3) and 3'-O-desmethyl-1-epipreussomerin C (4) have been isolated from liquid cultures of the coprophilous fungus Sporormiella vexans (JS 306). The structures of these new metabolites were elucidated on the basis of MS and NMR analysis. Compounds 1 and 4 show antifungal activity against competitor fungi, as well as antibacterial effects.

Antifungal and antibacterial metabolites from a sclerotium-colonizing isolate of Mortierella vinacea.

The known compound methyl 2,4-dihydroxy-3,5,6-trimethylbenzoate (1) and three new related metabolites, which we have named mortivinacins A (2), B (3), and C (4), were identified as metabolites of the fungus Mortierella vinacea. Nicotinic acid (5) was also encountered. This isolate of M. vinacea was obtained from an Aspergillus flavus sclerotium during field studies of sclerotium longevity in soil. Compounds 1-5 were isolated by chromatographic fractionation of organic extracts from M. vinacea solid-substrate fermentation cultures, and the structures were assigned by analysis of NMR and MS data. Compounds 1, 2, and 5 were responsible for the antibacterial and antifungal activities of the extract.

Arugosin F: a new antifungal metabolite from the coprophilous fungus Ascodesmis sphaerospora.

Chemical studies of the coprophilous fungus Ascodesmis sphaerospora (JS 247) have led to the isolation of arugosin F (1), a new antifungal and antibacterial metabolite. The structure was determined based on NMR and MS data and on comparison with data for known members of the arugosin class. A known xanthone (2) was also isolated.

Antifungal metabolites (monorden, monocillin IV, and cerebrosides) from Humicola fuscoatra traaen NRRL 22980, a mycoparasite of Aspergillus flavus sclerotia.

The mycoparasite Humicola fuscoatra NRRL 22980 was isolated from a sclerotium of Aspergillus flavus that had been buried in a cornfield near Tifton, Ga. When grown on autoclaved rice, this fungus produced the antifungal metabolites monorden, monocillin IV, and a new monorden analog. Each metabolite produced a clear zone of inhibition surrounding paper assay disks on agar plates seeded with conidia of A. flavus. Monorden was twice as inhibitory to A. flavus mycelium extension (MIC > 28 microg/ml) as monocillin IV (MIC > 56 microg/ml). Cerebrosides C and D, metabolites known to potentiate the activity of cell wall-active antibiotics, were separated from the ethyl acetate extract but were not inhibitory to A. flavus when tested as pure compounds. This is the first report of natural products from H. fuscoatra.

New p-terphenyl and polyketide metabolites from the sclerotia of Penicillium raistrickii.

Three new p-terphenyls (1-3), a new xanthone derivative (4), and two known fungal metabolites (5 and 6) have been isolated from the sclerotia of Penicillium raistrickii (NRRL 2039). The structures for 3,3"-dihydroxy-6'-desmethylterphenyllin (1); 3'-demethoxy-6'-desmethyl-5'-methoxycandidusin B (2); 6'-desmethylcandidusin B (3); and 1,3,5, 6-tetrahydroxy-8-methylxanthone (4) were determined on the basis of HRMS and NMR data. Although compounds 1 and 4 exhibited mild antiinsectan and antibacterial activity, griseofulvin (5) was responsible for most of the activity of the sclerotial extract in dietary assays against the corn earworm Helicoverpa zea.

Mollenines A and B: new dioxomorpholines from the ascostromata of Eupenicillium molle.

Two new dioxomorpholines (1 and 2) have been isolated from the sclerotioid ascostromata of Eupenicillium molle (NRRL 13062). Their structures were determined by analysis of NMR data. Mollenine A (1) exhibited moderate cytotoxicity and antibacterial activity, but neither compound displayed significant antiinsectan activity.

Anserinones A and B: new antifungal and antibacterial benzoquinones from the coprophilous fungus Podospora anserina.

Two new benzoquinones with antifungal, antibacterial, and cytotoxic activities have been isolated from liquid cultures of the coprophilous fungus Podospora anserina. The structures of anserinones A (1) and B (2) were assigned on the basis of MS and NMR results, and the absolute stereochemistry of 2 was deduced by analysis of 1H-NMR data for its (R)- and (S)-2-phenylbutyryl ester derivatives.

Sclerotiamide: a new member of the paraherquamide class with potent antiinsectan activity from the sclerotia of Aspergillus sclerotiorum.

Sclerotiamide (1), a new fungal natural product related to the paraherquamides, was isolated by bioassay-guided fractionation of antiinsectan organic extracts from the sclerotia of Aspergillus sclerotiorum (NRRL 5167). The structure was determined primarily through 1H-NMR, 13C-NMR, HMQC, and HMBC experiments. Sclerotiamide causes significant mortality and unusual physiological effects in dietary assays against the corn earworm Helicoverpa zea.

Ochratoxin A: an antiinsectan metabolite from the sclerotia of Aspergillus carbonarius NRRL 369.

Ochratoxin A, a known mycotoxin with demonstrated toxicity to insects, has been isolated from the sclerotia of the fungus Aspergillus carbonarius NRRL 369. The sclerotia, harvested from a solid substrate fermentation of corn kernels at 28 degrees C, produced quantities of ochratoxin A exceeding 50 ppm/g dry weight of sclerotia. Evidence is presented that ochratoxin A accounts for the activity of the methanol extract against larvae of the detritivorous beetle Carpophilus hemipterus (Nitidulidae) (75% reduction in feeding rate) and corn ear worm Helicoverpa zea (50% mortality with 99% reduction in weight gain among surviving larvae) when incorporated into a pinto bean diet at levels less than those occurring naturally in the sclerotia.

Cercophorins A-C: novel antifungal and cytotoxic metabolites from the coprophilous fungus Cercophora areolata.

Cercophorins A-C (3-5), three novel isocoumarin derivatives with antifungal and cytotoxic activities, have been isolated from the coprophilous fungus Cercophora areolata (JS 166 = UAMH 7495), a colonist of porcupine dung. Two additional new isocoumarins, decarboxy-citrinone (1) and 4-acetyl-8-hydroxy-6-methoxy-5-methylisocoumarin (2), and a known tricothecene mycotoxin, roridin E (6), were also obtained from this species. Compounds 1-6 were isolated from ethyl acetate extracts of mycelia and liquid cultures of C. areolata through bioassay-guided fractionation and are the first metabolites to be reported from a member of the genus Cercophora. Their structures were assigned on the basis of MS, selective INEPT, and 2D-NMR experiments.

Structure--activity relationships of the didemnins.

Bioactivities of 42 didemnin congeners, either isolated from the marine tunicates Trididemnun solidum and Aplidium albicans or prepared synthetically and semisynthetically, have been compared. The growth inhibition of various murine and human tumor cells and plaque reduction of HSV-1 and VSV grown on cultured mammalian cells were used to assess cytotoxicity and antiviral activity. Biochemical assays for macromolecular synthesis (protein, DNA, and RNA) and enzyme inhibition (dihydrofolate reductase, thymidylate synthase, DNA polymerase, RNA polymerase, and topoisomerases I and II) were also performed to specify the mechanisms of action of each analogue. Immunosuppressive activity of the didemnins was determined using a mixed lymphocyte reaction (MLR) assay. These assays revealed that the native cyclic depsipeptide core is an essential structural requirement for most of the bioactivites of the didemnins, especially for cytotoxicities and antiviral activities. The linear side-chain portion of the peptide can be altered with a gain, in some cases, of bioactivities. In particular, dehydrodidemnin B, tested against several types of tumor cells and in in vivo studies in mice, as well as didemnin M, tested for the mixed lymphocyte reaction and graft vs host reaction in murine systems, showed remarkable gains in their in vitro and in vivo activities compared to didemnin B.

Polytolypin, a new antifungal triterpenoid from the coprophilous fungus Polytolypa hystricis.

Polytolypin [1], a new pentacyclic triterpenoid exhibiting antifungal and antibiotic activity, has been isolated from cultures of Polytolypa hystricis (JS189), a fungal colonist of porcupine dung. Two known compounds [2 and 3] were also isolated. Polytolypin was obtained by chromatographic fractionation of the EtOAc extract of P. hystricis liquid cultures, and the structure was assigned on the basis of 2D nmr and hrms data.

Aflavinines and other antiinsectan metabolites from the ascostromata of Eupenicillium crustaceum and related species.

This report describes the distribution of antiinsectan metabolites present in sclerotioid ascostromata produced by representative strains of Eupenicillium crustaceum and fungal taxa that are considered to be closely related. The hexane and chloroform extracts of E. crustaceum NRRL 3332 displayed significant antiinsectan activity in assays against the corn earworm, Helicoverpa zea. The major metabolite accounting for this antiinsectan activity was a known aflavinine analog, 10,23-dihydro-24,25-dehydroaflavinine, occurring at approximately 2.8 mg/g of dry ascostromata. In dietary assays at ca. 3,000 ppm, a 79% reduction in weight gain and a 42% reduction in feeding rate were observed in H. zea and Carpophilus hemipterus larvae, respectively. A new aflavinine analog, 10,23,24,25-tetrahydro-24-hydroxyaflavinine, was also identified. These aflavinine compounds are the first to be reported from a fungal genus other than Aspergillus. New macrophorin-type metabolites accounted for the antiinsectan activity of ascostromata produced by E. crustaceum NRRL 22307, which produced no aflavinines, while Eupenicillium molle NRRL 13062 produced both aflavinines and macrophorins. Sclerotia produced by Penicillium gladioli NRRL 938, NRRL 939, and QM 2743, a fungus reported to be conspecific with the anamorph of E. crustaceum, produced neither aflavinines nor macrophorins. Eupenicillium reticulisporum NRRL 3446 produced the aflavinine analog 10,23-dihydro-24,25-dehydroaflavinine and an unrelated compound called pyripyropene A, a potent inhibitor of acyl-coenzyme A-cholesterol acyltransferase. Eupenicillium abidjanum NRRL 5809, reported to be conspecific with E. reticulisporum, produced neither of these compounds. The Eupenicillium species that produced aflavinines are also known for their ability to grow rapidly with reduced water activity.

Anguillosporal, a new antibacterial and antifungal metabolite from the freshwater fungus Anguillospora longissima.

Anguillosporal [1], a new antifungal and antibacterial metabolite, has been isolated from the freshwater fungus Anguillospora longissima (CS-869-1A). Its structure was determined as 2,4-dihydroxy-3-ethyl-6-(1'-methylpentyl)-benzaldehyde on the basis of ms, 1H-nmr, and 13C-nmr data.

Terezines A-D: new amino acid-derived bioactive metabolites from the coprophilous fungus Sporormiella teretispora.

Four new antifungal compounds, terezines A-D [1-4], have been isolated from liquid cultures of the coprophilous fungus Sporormiella teretispora by preparative tlc and hplc. The structures of these compounds were determined on the basis of nmr and ms data. The known fungal metabolite hyalopyrone [6] was also isolated from S. teretispora.