Acetylcholinesterase inhibitors from a marine fungus Talaromyces sp. strain LF458.

Two new oxaphenalenone dimers, talaromycesone A (1) and talaromycesone B (2), and a new isopentenyl xanthenone, talaroxanthenone (3), together with six known diphenyl ether derivatives, e.g., Δ(1',3'),-1'-dehydroxypenicillide (4), 1',2'-dehydropenicillide (5), vermixocin A (6), vermixocin B (7), 3'-methoxy-1'2'-dehydropenicillide (8), and AS-186c (9), were isolated from the culture broth and mycelia of a marine fungus Talaromyces sp. strain LF458. Compound 2 represents the first example of 1-nor oxaphenalenone dimer carbon skeleton. All isolated compounds were subjected to bioactivity assays. Compounds 1, 2, and 9 exhibited potent antibacterial activities with IC50 3.70, 17.36, and 1.34 µM, respectively, against human pathogenic Staphylococcus strains. Compounds 1, 3, and 9 displayed potent acetylcholinesterase inhibitory activities with IC50 7.49, 1.61, and 2.60 µM, respectively. Interestingly, phosphodiesterase PDE-4B2 was inhibited by compounds 3 (IC50 7.25 µM) and 9 (IC50 2.63 µM).

Calcarides A-E, antibacterial macrocyclic and linear polyesters from a Calcarisporium strain.

Bioactive compounds were detected in crude extracts of the fungus, Calcarisporium sp. KF525, which was isolated from German Wadden Sea water samples. Purification of the metabolites from the extracts yielded the five known polyesters, 15G256α, α-2, ß, ß-2 and π (1-5), and five new derivatives thereof, named calcarides A-E (6-10). The chemical structures of the isolated compounds were elucidated on the basis of one- and two-dimensional NMR spectroscopy supported by UV and HRESIMS data. The compounds exhibited inhibitory activities against Staphylococcus epidermidis, Xanthomonas campestris and Propionibacterium acnes. As the antibacterial activities were highly specific with regard to compound and test strain, a tight structure-activity relationship is assumed.

Calcaripeptides A-C, cyclodepsipeptides from a Calcarisporium strain.

The isolation and structure elucidation of the novel calcaripeptides A (1), B (2), and C (3) and studies on their biosynthetic origin are described. The calcaripeptides were identified from Calcarisporium sp. strain KF525, which was isolated from the German Wadden Sea. Compounds 1-3 are macrocyclic structures composed of a proline and a phenylalanine residue as well as a nonpeptidic substructure. Structure elucidation was achieved by applying one- and two-dimensional NMR spectroscopy supported by high-resolution mass spectrometry. X-ray crystallography was performed to determine the relative configuration of 1. The absolute configuration of 1 was assigned by HPLC of the amino acids after hydrolysis of the molecule and derivatization with chiral agents. Studies on the biosynthesis by feeding ¹³C-labeled substrates revealed that the nonpeptidic part of 1 originates from acetate and l-methionine. The involvement of a hybrid between a polyketide synthase and a nonribosomal peptide synthetase in the biosynthesis of the calcaripeptides is discussed.

Helicusin E, isochromophilone X and isochromophilone XI: new chloroazaphilones produced by the fungus Bartalinia robillardoides strain LF550.

Microbial studies of the Mediterranean sponge Tethya aurantium led to the isolation of the fungus Bartalinia robillardoides strain LF550. The strain produced a number of secondary metabolites belonging to the chloroazaphilones. This is the first report on the isolation of chloroazaphilones of a fungal strain belonging to the genus Bartalinia. Besides some known compounds (helicusin A (1) and deacetylsclerotiorin (2)), three new chloroazaphilones (helicusin E (3); isochromophilone X (4) and isochromophilone XI (5)) and one new pentaketide (bartanolide (6)) were isolated. The structure elucidations were based on spectroscopic analyses. All isolated compounds revealed different biological activity spectra against a test panel of four bacteria: three fungi; two tumor cell lines and two enzymes.

Diacidene, a polyene dicarboxylic acid from a Micromonospora isolate from the German Wadden Sea.

Micromonospora sp. strain DB620 was isolated from a Wadden Sea sediment sample collected near Büsum (Germany) and is closely related (99% 16S-rRNA gene sequence similarity) to Micromonospora coxensis strain MTCC8093. It produced a new polyene dicarboxylic acid named diacidene (1) and in addition a derivative of chorismic acid, the known 3-[(1-carboxyvinyl)oxy]benzoic acid. The structure elucidation of 1 was achieved by applying different 1D and 2D NMR techniques as well as mass spectrometry and UV spectroscopy.

Geranylphenazinediol, an acetylcholinesterase inhibitor produced by a Streptomyces species.

Geranylphenazinediol (1), a new phenazine natural product, was produced by the Streptomyces sp. strain LB173, which was isolated from a marine sediment sample. The structure was established by analysis of NMR and MS data. 1 inhibited the enzyme acetylcholinesterase in the low micromolar range and showed weak antibacterial activity. In order to get a more detailed picture of the activity profile of 1, its inhibitory potential was compared to that of related structures.

Abenquines A-D: aminoquinone derivatives produced by Streptomyces sp. strain DB634.

New bioactive secondary metabolites, called abenquines, were found in the fermentation broth of Streptomyces sp. strain DB634, which was isolated from the soils of the Chilean highland of the Atacama Desert. They are composed of an amino acid linked to an N-acetyl-aminobenzoquinone. Isolation of the abenquines (1-4), their structure elucidation by NMR analysis and MS, as well as the kinetics of their production are presented. The abenquines show inhibitory activity against bacteria, dermatophytic fungi and phosphodiesterase type 4b. The amino acid attached to the quinone is relevant to the enzyme inhibitory activity.

Szentiamide, an N-formylated cyclic depsipeptide from Xenorhabdus szentirmaii DSM 16338T.

Szentiamide (1) a new cyclic hexadepsipeptide was isolated from the culture broth of the entomopathogenic bacterium Xenorhabdus szentirmaii DSM 16338T. The structure was elucidated by analysis of one- and two-dimensional NMR spectra and high resolution mass spectrometry. The amino acids were determined to be D-leucine, L-threonine, D-phenylalanine, D-valine, L-tyrosine and L-tryptophane after hydrolysis and derivatization with D-FDVA [Nalpha-(2,4-dinitro-5-fluorophenyl)-D-valinamide].

Phylogenetic identification of fungi isolated from the marine sponge Tethya aurantium and identification of their secondary metabolites.

Fungi associated with the marine sponge Tethya aurantium were isolated and identified by morphological criteria and phylogenetic analyses based on internal transcribed spacer (ITS) regions. They were evaluated with regard to their secondary metabolite profiles. Among the 81 isolates which were characterized, members of 21 genera were identified. Some genera like Acremonium, Aspergillus, Fusarium, Penicillium, Phoma, and Trichoderma are quite common, but we also isolated strains belonging to genera like Botryosphaeria, Epicoccum, Parasphaeosphaeria, and Tritirachium which have rarely been reported from sponges. Members affiliated to the genera Bartalinia and Volutella as well as to a presumably new Phoma species were first isolated from a sponge in this study. On the basis of their classification, strains were selected for analysis of their ability to produce natural products. In addition to a number of known compounds, several new natural products were identified. The scopularides and sorbifuranones have been described elsewhere. We have isolated four additional substances which have not been described so far. The new metabolite cillifuranone (1) was isolated from Penicillium chrysogenum strain LF066. The structure of cillifuranone (1) was elucidated based on 1D and 2D NMR analysis and turned out to be a previously postulated intermediate in sorbifuranone biosynthesis. Only minor antibiotic bioactivities of this compound were found so far.

Levantilides A and B, 20-membered macrolides from a Micromonospora strain isolated from the Mediterranean deep sea sediment.

Two new 20-membered macrolides, levantilide A and B, were isolated from the Micromonospora strain M71-A77. Strain M71-A77 was recovered from an Eastern Mediterranean deep-sea sediment sample and revealed to produce the levantilides under in situ salinity of 38.6 ‰. The chemical structures of the levantilides were elucidated on the basis of different one- and two- dimensional NMR experiments. Levantilide A exhibits a moderate antiproliferative activity against several tumor cell lines.

Eutypoids B-E produced by a Penicillium sp. strain from the North Sea.

Crude extracts of the Penicillium sp. strain KF620 isolated from the North Sea showed antimicrobial activities against Xanthomonas campestris and Candida glabrata. Purification of the extracts led to the isolation of the new aromatic butenolides eutypoids B (1), C (2), D (3), and E (4). Their structures were elucidated by NMR spectroscopy and supported by HRESIMS and UV data. The antibacterial activity of the crude extracts was due to the presence of the known diketopiperazine fellutanine (cyclo(Trp-Trp)). The eutypoids were neither cytotoxic nor antibacterial, but inhibited the activity of glycogen synthase kinase-3ß.

Nocapyrones A-D, gamma-pyrones from a Nocardiopsis strain isolated from the marine sponge Halichondria panicea.

Four new gamma-pyrones, nocapyrones A-D (1-4), were isolated from an organic extract of the Nocardiopsis strain HB383, which was isolated from the marine sponge Halichondria panicea. These are the first gamma-pyrones reported from a Nocardiopsis strain. The structures were elucidated on the basis of one- and two-dimensional NMR experiments and supported by HPLC-UV/MS and HRESIMS analyses. The biosynthesis of nocapyrone A was investigated by feeding experiments with (13)C-labeled compounds. In addition, one diketopiperazine, which was only known as a synthetic compound before, was isolated. The bioactivies of 1, 2, and the diketopiperazine were evaluated in a panel of assays.

Mayamycin, a cytotoxic polyketide from a Streptomyces strain isolated from the marine sponge Halichondria panicea.

A new benz[a]anthracene derivative called mayamycin (1) was identified in cultures of Streptomyces sp. strain HB202, which was isolated from the marine sponge Halichondria panicea and selected because of its profound antibiotic activity. The ability to produce aromatic polyketides was indicated by genetic analyses, demonstrating the presence of a type II polyketide synthase. The production of mayamycin (1) was induced by variation of the culture conditions. The structure of 1 was elucidated by HPLC-UV/MS and NMR spectroscopy. Mayamycin (1) exhibited potent cytotoxic activity against eight human cancer cell lines and showed activity against several bacteria including antibiotic-resistant strains.

Myxotyrosides A and B, Unusual rhamnosides from Myxococcus sp.

Myxobacteria are gliding bacteria of the delta-subdivision of the Proteobacteria and known for their unique biosynthetic capabilities. Two examples of a new class of metabolites, myxotyrosides A (1) and B (2), were isolated from a Myxococcus sp. The myxotyrosides have a tyrosine-derived core structure glycosylated with rhamnose and acylated with unusual fatty acids such as (Z)-15-methyl-2-hexadecenoic and (Z)-2-hexadecenoic acid. The fatty acid profile of the investigated Myxococcus sp. (strain 131) is that of a typical myxobacterium with a high similarity to those described for M. fulvus and M. xanthus, with significant concentrations of neither 15-methyl-2-hexadecenoic acid nor 2-hexadecenoic acid being detected.

Phenylnannolones A-C: biosynthesis of new secondary metabolites from the myxobacterium Nannocystis exedens.

Myxobacteria are gliding bacteria that belong to the delta-Proteobacteria and are known for their unique biosynthetic capabilities. Among myxobacteria, Nannocystis spp. are most closely related to marine myxobacteria and their secondary metabolism has hardly been investigated. Phenylnannolones A (1), B (2) and C (3) were obtained from a culture of Nannocystis exedens that was isolated from the intertidal region of Crete. Compound 1 had inhibitory activity toward the ABCB1 gene product P-glycoprotein and reversed daunorubicin resistance in cultured cancer cells. Phenylnannolone A has an unusual structural architecture; it is composed of an ethyl-substituted polyene chain linked to a pyrone moiety on one side and to a phenyl ring on the other. The investigation of the biosynthesis with labelled precursors revealed acetate, butyrate and phenylalanine as building blocks for 1. The labelling pattern suggested novel biochemical reactions for the biosynthesis of the starter unit.

Myxochromide B3, a new member of the myxochromide family of secondary metabolites.

Myxochromides are cyclic depsipeptides with an unsaturated polyketide side chain, which have been reported from different myxobacterial species, e.g., Myxococcus xanthus and Stigmatella aurantiaca. To date, myxochromides are subdivided into the groups A and S, according to their peptidic core structure. The peptide moiety of the new myxochromide B3 (1), which was isolated from a myxobacterial strain of the genus Myxococcus, differs from that of myxochromides A and S. Compound 1 thus is the first representative of a new group of myxochromides. For myxochromide A3 (2) the complete and assigned spectroscopic data are described. For the structure elucidation one- and two-dimensional NMR spectroscopy as well as mass spectrometry have been applied. Configurational analysis has been accomplished by chiral GC-MS and HPLC.

The genus Hypericum--a valuable resource of anti-Staphylococcal leads.

In the present study, extracts of 34 species and varieties of the genus Hypericum were screened for activity against a clinical isolate of methicillin-resistant Staphylococcus aureus, which in addition possessed a multidrug efflux mechanism conferring a high level of resistance to therapeutically useful antibiotics. Thirty-three of the 34 chloroform extracts showed significant activity in a disk diffusion assay, and five extracts had minimum inhibitory concentrations of 64 microg/ml, indicating that this genus has great potential to yield compounds with potent activity against multidrug-resistant bacteria.