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The genus Sphaerostilbella comprises fungi that colonize basidiomata of wood-inhabiting fungi, including important forest pathogens. Studies of fermentation cultures of an isolate (TFC201724) collected on the foothills of Himalayas, and closely related to S. broomeana isolates from Europe, led to the identification of a new cyclic octapeptide along with two closely related analogues ( 1 - 3 ) and four dioxopiperazines ( 4 - 7 ). The structure of the lead compound, broomeanamide A ( 1 ), was assigned mainly by analysis of 2D NMR and HRESIMS data. The structure consisted of one unit each of N -MeVal, Ala, N -MePhe, Pro, Val, and Ile and two N -MeLeu units. The amino acid sequence was determined on the basis of 2D NMR and HRESIMSMS data. NMR and HRMS data revealed that the other two new peptides have the same amino acid composition except that the Ile unit was replaced with Val in one instance ( 2 ) and the N -MeVal unit was replaced with Val in the other ( 3 ). The absolute configuration of 1 was assigned by analysis of the acid hydrolysate by application of Marfey's method using both C 18 and C 3 bonded-phase columns. Broomeanamide A ( 1 ) showed antifungal activity against Cryptococcus neoformans and Candida albicans , with MIC values of 8.0 and 64 μg/mL, respectively.

Campafungin A is a polyketide that was recognized in the Candida albicans fitness test due to its antiproliferative and antihyphal activity. Its mode of action was hypothesized to involve inhibition of a cAMP-dependent PKA pathway. The originally proposed structure appeared to require a polyketide assembled in a somewhat unusual fashion. However, structural characterization data were never formally published. This background stimulated a reinvestigation in which campafungin A and three closely related minor constituents were purified from fermentations of a strain of the ascomycete fungus Plenodomus enteroleucus . Labeling studies, along with extensive NMR analysis, enabled assignment of a revised structure consistent with conventional polyketide synthetic machinery. The structure elucidation of campafungin A and new analogues encountered in this study, designated here as campafungins B, C, and D, is presented, along with a proposed biosynthetic route. The antimicrobial spectrum was expanded to methicillin-resistant Staphylococcus aureus , Candida tropicalis , Candida glabrata , Cryptococcus neoformans , Aspergillus fumigatus , and Schizosaccharomyces pombe , with MICs ranging as low as 4-8 μg mL -1 in C. neoformans . Mode-of-action studies employing libraries of C. neoformans mutants indicated that multiple pathways were affected, but mutants in PKA/cAMP pathways were unaffected, indicating that the mode of action was distinct from that observed in C. albicans.

During investigation of the secondary metabolism of four strains of Penicillium arenicola , two new depsides, arenicolins A ( 1 ) and B ( 2 ), were isolated and characterized. Their structures were established mainly by analysis of NMR and HRMS data and by comparison with known compounds. These depsides incorporate intriguing structural features, including dual alkyl side chains and a C -glycosyl unit, with 1 also containing an acylated 2-hydroxymethyl-4,5,6-trihydroxycyclohexenone moiety. Although the arenicolins were produced by all strains tested, arenicolin A ( 1 ) was obtained using only one of five medium compositions employed, while arenicolin B ( 2 ) was produced in all media tested. Neither compound showed antibacterial or antifungal activity, but 1 exhibited cytotoxicity toward mammalian cell lines, including colorectal carcinoma (HCT-116), neuroblastoma (IMR-32), and ductal carcinoma (BT-474), with IC 50 values of 7.3, 6.0, and 9.7 μM, respectively.

In the course of our studies of coprophilous fungi as sources of antifungal agents, a strain of an undescribed species in the genus Niesslia (TTI-0426) was isolated from horse dung collected in Texas. An extract from fermentation cultures of this strain afforded two new antifungal wortmannin derivatives, wortmannins C and D (1 and 2), as well as four additional new related compounds, wortmannines B1-B4 (3-6), containing an unusual ring system. The structures of these metabolites were established mainly by analysis of HRESIMS and 2D NMR data. Relative configurations were assigned using NOESY data, and the structure assignments were supported by NMR comparison with similar compounds. Wortmannins C and D showed activity against Cryptococcus neoformans and Candida albicans in disk assays, but low MIC potency observed for 1 was suggested to be due in part to efflux processes on the basis of assay results for a Schizosaccharomyces pombe efflux mutant in comparison to wild-type.

Auxarthrones A-E (1-5), five new phenalenones, and two new naturally occurring cyclic tetrapeptides, auxarthrides A (7) and B (8), were obtained from three different solvent extracts of cultures of the coprophilous fungus Auxarthron pseudauxarthron. Auxarthrones C (3) and E (5) possess an unusual 7a,8-dihydrocyclopenta[a]phenalene-7,9-dione ring system that has not been previously observed in natural products. Formation of 1-5 was found to be dependent on the solvent used for culture extraction. The structures of these new compounds were elucidated primarily by analysis of NMR and MS data. Auxarthrone A (1) was obtained as a mixture of chromatographically inseparable racemic diastereomers (1a and 1b) that cocrystallized, enabling confirmation of their structures by X-ray crystallography. The absolute configurations of 7 and 8 were assigned by analysis of their acid hydrolysates using Marfey's method. Compound 1 displayed moderate antifungal activity against Cryptococcus neoformans and Candida albicans, but did not affect human cancer cell lines.

Studies of the genome-sequenced, flutimide-producing coprophilous fungus Delitschia confertaspora (ATCC 74209), originally obtained from a sample of rock hyrax (Procavia capensis) dung collected in Namibia, led to the discovery of three new highly aromatic natural products named delicoferones A-B (1-2) and fimetarone B (3). The new benzophenone derivatives 1 and 2 have a somewhat unusual skeleton that incorporates three aromatic rings linked via two ketone carbonyl groups, while 3 contains a spiro[chroman-3,7'-isochromene]-4,6'(8'H) skeleton reported only once previously. The structures of these compounds were assigned mainly by analysis of 2D NMR and HRESITOFMS data.

Eleven emestrin-type epipolythiodioxopiperazines, including four new compounds, emestrins H-K (1-4), were isolated from the crude extracts of two strains of the coprophilous fungus Podospora australis. The structures of 1-4 were established primarily by analysis of NMR data, and the absolute configuration of C-6 in 1 was independently assigned using the modified Mosher method. Four of the known emestrins obtained (emestrins C-E and MPC1001C) were found to selectively inhibit the growth of Cryptococcus neoformans. These results also represent the first report of chemistry from any strain of P. australis.

Seven new polyketide metabolites (disseminins A-E, 1-5, and spiciferones D and E, 7 and 8) were obtained from cultures of a fungicolous isolate of Pestalotiopsis disseminata (NRRL 62562), together with a related compound (6) previously known only as a semisynthetic product. Structures were determined mainly by analysis of HRMS and NMR data. Biogenetically related compounds 1 and 2 possess uncommon bis-tetrahydrofuran and dioxabicyclo[3.2.1]octane ring systems, respectively. X-ray crystallographic analysis of the p-bromobenzoate derivative of 1 confirmed the structure and enabled assignment of its absolute configuration.

Studies of the coprophilous fungus Hypocopra rostrata (TTI-0009, NRRL 66178) isolated from a sample of horse dung collected in Texas led to the isolation of three new sesquiterpenoids that we named hypocoprins A-C (1-3), together with the known fungal metabolite helvolic acid. The new metabolites have a distinctive ring system consisting of fused cyclopropane and cyclodecene units not previously reported from a fungal source. Compounds 1 and 3 moderately inhibited growth of Staphylococcus aureus. The structures of these metabolites were assigned mainly by analysis of 2D NMR and HRESITOFMS data. Relative and absolute configurations were assigned by interpretation of NMR J-values and NOESY data and by application of Mosher's method. These results represent the first report of chemistry from any strain of the genus Hypocopra.

Continuing investigation of fractions from a supercritical fluid extract of Chinese licorice (Glycyrrhiza uralensis) roots has led to the isolation of 12 phenolic compounds, of which seven were described previously from this extract. In addition to these seven metabolites, four known components, 1-methoxyerythrabyssin II (4), 6,8-diprenylgenistein, gancaonin G (5), and isoglycyrol (6), and one new isoflavan, licorisoflavan C (7), were characterized from this material for the first time. Treatment of licoricidin (1) with palladium chloride afforded larger amounts of 7 and also yielded two new isoflavans, licorisoflavan D (8), which was subsequently detected in the licorice extract, and licorisoflavan E (9). Compounds 1-9 were evaluated for their antibacterial activities against the cariogenic Streptococcus mutans and the periodontopathogenic Porphyromonas gingivalis. Licoricidin (1), licorisoflavan A (2), and 7-9 showed antibacterial activity against P. gingivalis (MICs of 1.56-12.5 μg/mL). The most potent activity against S. mutans was obtained with 7 (MIC of 6.25 μg/mL), followed by 1 and 9 (MIC of 12.5 μg/mL). This study provides further evidence for the therapeutic potential of licorice extracts for the treatment and prevention of oral infections.

Seven new compounds (aflaquinolones A-G; 1-7) containing dihydroquinolin-2-one and terpenoid units have been isolated from two different fungal sources. Two of these metabolites (1 and 2) were obtained from a Hawaiian fungicolous isolate of Aspergillus sp. (section Flavipedes; MYC-2048 = NRRL 58570), while the others were obtained from a marine Aspergillus isolate (SF-5044) collected in Korea. The structures of these compounds were determined mainly by analysis of NMR and MS data. Relative and absolute configurations were assigned on the basis of NOESY data and (1)H NMR J-values, comparison of calculated and experimental ECD spectra, and analysis of a Mosher's ester derivative of 2. Several known compounds, including alantrypinone, aspochalasins I and J, methyl 3,4,5-trimethoxy-2((2-((3-pyridinylcarbonyl)amino)benzoyl)amino)benzoate, and trans-dehydrocurvularin were also encountered in the extract of the Hawaiian isolate.

Phomalevones A-C (1-3), three new com-pounds with bis-dihydroxanthone and bis-benzophenone systems, were isolated from cultures of a Hawaiian isolate of Phoma sp. (MYC-1734 = NRRL 39060; Cucurbitariaceae). The structures of 1-3 were determined by analysis of NMR and MS data. The absolute configurations of the sp(3) stereocenters in the monomeric unit of 1 were assigned by application of Mosher's method, and overall absolute configurations were proposed on the basis of ECD data using both computational methods and comparisons with literature data for model compounds. All three compounds showed antibacterial activity, and compounds 2 and 3 also exhibited antifungal effects.

Hymenopsin A (1), hymenopsin B (2), and a new macrophorin analogue, 2',3'-epoxy-13-hydroxy-4'-oxomacrophorin A (3), have been isolated from a fungicolous isolate of Hymenopsis sp. (MYC-1703; NRRL 37638). The structures and relative configurations of these compounds were assigned on the basis of 2D NMR and MS data, and the identity of 1 was confirmed by X-ray crystallographic analysis. The absolute configuration of 2 was proposed on the basis of CD analysis using both empirical and computational methods. Compounds 2 and 3 showed antibacterial activity against Staphylococcus aureus and Bacillus subtilis. Compound 3 was also active against Aspergillus flavus and Fusarium verticillioides.

Four new decarestrictine analogues (botryolides A-D; 1- 4), a biosynthetically related gamma-lactone (botryolide E; 5), and the known compounds decarestrictine D ( 6) and sterigmatocystin have been isolated from cultures of a fungicolous isolate of Botryotrichum sp. (NRRL 38180). The structures of these compounds were determined by analysis of 2D NMR and ESIMS data. The relative configurations of 1- 5 were established on the basis of NMR data and/or X-ray diffraction analysis, while the absolute configuration of 1 was assigned using the modified Mosher method.

In addition to 10 known compounds (7- 16), one new brominated diterpene, 10-hydroxykahukuene B (1), two new sesquiterpenes, 9-deoxyelatol (2) and isodactyloxene A (3), one new brominated C 15-acetogenin, laurenmariallene (4), and two new naturally occurring halogenated sesquiterpenes (5 and 6) that were previously obtained as intermediates in a biomimetic synthetic study of rhodolaureol and rhodolauradiol have been isolated and identified from the organic extract of the marine red alga Laurencia mariannensis. The structures of these compounds were established by spectroscopic methods. The antibacterial and antifungal activities of new compounds 1-4 were evaluated.

Seven new aroyl uridine derivatives (kipukasins A-G; 1-7) were isolated from solid-substrate fermentation cultures of two different Hawaiian isolates of Aspergillus versicolor. The structures of compounds 1-7 were determined by analysis of NMR and MS data. The nucleoside portion of lead compound 1 was assigned as uracil-1-beta-D-ribofuranoside by spectral comparison with an authentic standard. The bioactivity of the original A. versicolor extracts was accounted for mainly by the presence of the known metabolite sterigmatocystin, but kipukasins A and B showed modest activity in assays against Gram-positive bacteria.

Four new solanapyrone analogues (solanapyrones J-M; 1-4) have been isolated from an unidentified fungicolous fungus collected in Hawaii. The structures and relative configurations of these compounds were determined by analysis of 1D NMR, 2D NMR, and MS data. Solanapyrone J (1) showed antifungal activity against Aspergillus flavus and Fusarium verticillioides, while both 1 and 2 showed activity against Staphylococcus aureus and Candida albicans.

Four new triterpenoid glycosides, kolokosides A-D (1-4), along with the known compound 19,20-epoxycytochalasin N, were isolated from cultures of a Hawaiian wood-decay fungus (Xylaria sp.). The structures and relative configurations of 1-4 were determined primarily by analysis of NMR data, and the absolute configuration of 1 was assigned by application of the exciton chirality method. Compound 1 exhibited activity against Gram-positive bacteria.

Decaspirones A-E (1-5), five new compounds related to the palmarumycins, were isolated from cultures of the freshwater aquatic fungal species Decaisnella thyridioides. The known compound palmarumycin CP1 (6) was also obtained. The structures of 1-5 were determined by analysis of NMR and MS data, and their relative configurations were assigned by analysis of 1H NMR J-values and NOESY data. The structure of the lead compound 1 was confirmed by X-ray crystallographic analysis. Compounds 1-5 possess a trans ring fusion not previously reported in members of this structural class. The absolute configuration of 1 was assigned using the modified Mosher method. Compounds 1-5 showed potent antifungal and antibacterial activity.

Penifulvins B-E (2-5), four new sesquiterpenoids with a dioxa[5.5.5.6]fenestrane ring system, have been isolated from cultures of an isolate of Penicillium griseofulvum (NRRL 35584), together with a new silphinene derivative, 12-hydroxysilphinene-15-oic acid (6). Penifulvins B-E (2-5) are oxidized analogues of penifulvin A (1) and were identified by analysis of NMR and MS data. 12-Hydroxysilphinen-15-oic acid (6) is biogenetically similar, and penifulvins A-E are presumed to be derived from a silphinene precursor. The structures of 2-6, including absolute configuration, were assigned by analysis of NMR data and application of chemical methods.

A new 12-membered macrolide (chloriolide; 1) was obtained from solid-substrate fermentation cultures of Chloridium virescens var. chlamydosporum that was originally isolated from decayed wood. The structure of 1 was determined by analysis of 1D NMR, 2D NMR, and MS data and confirmed by X-ray crystallographic analysis. The absolute configuration of 1 was assigned by application of the modified Mosher method using the (R)- and (S)-MTPA derivatives of a rearrangement product obtained under standard acylation conditions. The assignment made by analysis of the corresponding Deltadelta values was verified by X-ray crystallographic analysis of the (S)-MTPA derivative.

Four new altenuene derivatives called dihydroaltenuenes A (1) and B (2) and dehydroaltenuenes A (3) and B (4), along with five known compounds, including isoaltenuene (5), altenuene (6), and 5'-epialtenuene (7), were isolated from cultures of an unidentified freshwater aquatic fungal species in the family Tubeufiaceae. The structures of 1-4 were determined by analysis of NMR and MS data. The relative stereochemistry was determined on the basis of (1)H NMR J-values and NOE data, while the absolute configuration of a representative member of the group (5) was assigned by CD spectral analysis of its bis-N,N-dimethylaminobenzoate derivative. Compounds 1, 3, 4, 5, and 6 showed antibiotic activity against Gram-positive bacteria.

Three new caryophyllene-type sesquiterpene alcohols, 6-hydroxypunctaporonin E (1), 6-hydroxypunctaporonin B (2), and 6-hydroxypunctaporonin A (3), have been isolated from cultures of the fungicolous fungus Pestalotiopsis disseminata. The structures of 1-3 were determined mainly by analysis of 1D and 2D NMR data. The structure and absolute configuration of 6-hydroxypunctaporonin E (1) was confirmed through X-ray crystallographic analysis of its mono-bromobenzoate derivative. Compounds 1 and 2 showed activity against Gram-positive bacteria.

Two new benzofuran-derived metabolites of polyketide origin called phaeofurans A and B (1 and 2), along with three sorbicillin analogues (3-5), have been obtained from a fungicolous isolate of the genus Phaeoacremonium (NRRL 32148). The structures were determined by analysis of MS and 2D NMR data. The antifungal effects of the extract were ascribed to the sorbicillin analogues.

Four new tetrahydropyran derivatives called ophiocerins A-D (1-4) and a new africane sesquiterpenoid (ophioceric acid; 5) have been isolated from cultures of the aquatic fungus Ophioceras venezuelense, together with the known compound regiolone. The structures and relative stereochemistry of these compounds were determined by analysis of 1D and 2D NMR data, while absolute stereochemical assignments for 1-4 were proposed by application of the exciton chirality CD method.

Three new oxalicine and decaturin analogues (6-8) have been isolated from organic extracts of Penicillium thiersii, along with the known compounds oxalicines A and B. These compounds (4-8) are members of a group of unique natural products containing terpenoid and pyridine moieties. The structures of the new compounds were elucidated by analysis of NMR and MS data. Most of these metabolites exhibit potent antiinsectan activity against the fall armyworm (Spodoptera frugiperda).

Communiols E-H (1-4), four new polyketide-derived natural products containing furanocyclopentane, furanocyclopentene, cyclopentene, or gamma-lactone moieties, have been isolated from two geographically distinct isolates of the coprophilous fungus Podospora communis. The structures of these compounds were determined by analysis of NMR and MS data.

Malettinins B-D (2-4), three new antimicrobial polyketide-derived metabolites related to the previously reported malettinin A (1), have been obtained from nonsporulating cultures of an isolate of Mycelia sterilia MYC-155 (= NRRL 29110) collected from colonies of Hypoxylon stromata. Malettinins B (2) and C (3) are partially reduced analogues of malettinin A and were identified by analysis of NMR and MS data. Malettinin D (4) is biogenetically similar, but possesses a new ring system, and the structure of 4 was established by single-crystal X-ray diffraction analysis.

Fermentation extracts of Cordyceps heteropoda (ARSEF #1880), an entomopathogenic fungus isolated from an Australian cicada, yielded a known antifungal compound, myriocin, and a complex microheterogeneous family of novel nonribosomal peptides, each containing two residues of alpha-aminoisobutyric acid (Aib). Structure elucidation of two major components of the peptide mixture, cicadapeptins I and II (1 and 2), was accomplished by amino acid analysis and various MS, 1-D NMR, and 2-D NMR experiments. Both compounds are acylated at the N-terminus by n-decanoic acid and amidated at the C-terminus by 1,2-diamino-4-methylpentane. The amino acid sequence of cicadapeptin I is N-terminus-Hyp-Hyp-Val-Aib-Gln-Aib-Leu-C-terminus. Ile substitutes for Leu in cicadapeptin II. To our knowledge, this is the first report from fungi of consecutive Hyp or Pro residues in a nonribosomal linear peptide. ROESY data indicated that the cicadapeptins adopt a helical conformation. Cicadapeptins I and II displayed antibacterial activity and limited antifungal activity.

Eight new polyketide metabolites, annularins A-H (1-8), along with the known compound (-)-(S)-p-hydroxyphenyllactic acid, were isolated from the organic extracts of the freshwater fungus Annulatascus triseptatus. Compounds 1-6 are 3,4,5-trisubstituted alpha-pyrones, and the fused bicyclic pyrone-furanone system in annularin F (6) has not been reported previously among natural products. Compounds 7 and 8 are 3,4-disubstituted alpha,beta-unsaturated gamma-lactones. Annularins A (1), B (2), C (3), and F (6) exhibited antibacterial activity.

Three new 3-substituted indole diterpenoids (thiersindoles A-C; 1-3) have been isolated from organic extracts of a new Penicillium species (P. thiersii). Their structures, including absolute stereochemistry, were determined by analysis of NMR data and application of Mosher's method. Thiersindoles A-C are biogenetically related to the aflavinines, although the [6,6,5] tricyclic diterpenoid skeleton in compounds 1 and 2 is unprecedented in any of the known members of this class.

Lowdenic acid (1), a new antifungal metabolite with an unusual structure and a mixed biogenetic origin, has been obtained from nonsporulating cultures of a previously undescribed Verticillium sp. (MYC-406 = NRRL 29280) that was isolated as a colonist of polypore basidiomata. The gross structure of 1 was proposed by analysis of NMR data and confirmed by X-ray diffraction analysis, which enabled assignment of relative stereochemistry. Compound 1 occurs as an equilibrium E/Z mixture. The known antifungal metabolite canescin A (2) was also isolated.

Four new rosigenin analogues (massarigenins A-D; 1-4) and two new aromatic polyketide-derived secondary metabolites (massarinins A and B; 6, 7) and have been isolated from the freshwater aquatic fungus Massarina tunicata. The structures of these compounds were determined primarily by analysis of NMR data, and that of compound 1 was verified by X-ray crystallography. The known compound 4-(2-hydroxybutynoxy)benzoic acid (11) was also obtained, and its absolute stereochemistry was assigned. Several of these metabolites showed antibiotic activity against Gram-positive bacteria.

Chemical studies of an organic extract from solid-substrate fermentations of the mycoparasitic fungus Humicola fuscoatra NRRL 22980, originally isolated as a colonist of Aspergillus flavus sclerotia, afforded two new unrelated compounds that we have named fuscoatroside (1) and fuscoatramide (2). The structures of these metabolites were elucidated by analysis of NMR and MS data. Fuscoatroside (1) is a triterpenoid glycoside that exhibited activity in antifungal assays against A. flavus. This extract also contained the known metabolites 7-deoxysterigmatocystin, sterigmatocystin, isosclerone, and decarestrictines A(1) and I.

Decipinin A (1), a new compound with antifungal and antibacterial activity, has been isolated from liquid cultures of the coprophilous fungus Podospora decipiens (JS 270). Two new tetracyclic sesquiterpene lactones, decipienolides A (2) and B (3), were also obtained from this isolate as an inseparable mixture of epimers that showed antibacterial activity. The structures of 1-3 were elucidated by analysis of 1D and 2D NMR data, aided by chemical shift comparisons to related compounds.

Eight new polyketide-derived metabolites [cladoacetals A and B (1 and 2), 3-(2-formyl-3-hydroxyphenyl)propionic acid (3), 3-deoxyisoochracinic acid (4), isoochracinol (5), 7-hydroxy-3-(2,3-dihydroxybutyl)-1(3H)-isobenzofuranone (6), (+)-cyclosordariolone (10), and altersolanol J (11)] and six known metabolites [two isomeric 1-(1,3-dihydro-4-hydroxy-1-isobenzofuranyl)butan-2,3-diols (7a/b), 7-hydroxy-1(3H)-isobenzofuranone (8), isoochracinic acid (9), altersolanol A (12), and macrosporin (13)] have been isolated from solid-substrate fermentation cultures of an undetermined fungicolous isolate (NRRL 29097) that resembles Cladosporium sp. All structures were assigned primarily by analysis of 1D and/or 2D NMR data. Five of the compounds showed antibacterial activity.

Five new natural products, phomadecalins A-D (1-4) and phomapentenone A (5), have been obtained from cultures of Phoma sp. (NRRL 25697), a fungal colonist isolated from the stromata of Hypoxylon sp. The structures of these compounds were elucidated through a series of 1D and 2D NMR experiments. Compounds 1-4 display activity against Gram-positive bacteria.