Biomedical subjects
Publications and source records attributed to Gabriele M König.
Chemical investigation of the marine-derived fungus Ascochyta salicorniae led to the isolation of two novel natural products, ascospiroketals A (1) and B (2). From a biosynthetic standpoint, the compounds possess new ring systems. [structure: see text].
The cyanobacterium Tychonema sp. produces the new cyclic hexapeptides brunsvicamide A-C (1-3). Brunsvicamide B (2) and C (3) selectively inhibit the Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB), a potential drug target for tuberculosis therapy for which no inhibitors are known to date. Brunsvicamide C contains an N-methylated N'-formylkynurenine moiety, a unique structural motif in cyclic peptides. The new peptides are related to the sponge-derived mozamides, supporting the suggestion that secondary metabolites of certain marine invertebrates are produced by associated microorganisms. Thus, microorganisms phylogenetically related to symbionts of marine invertebrates can be judged as a means to supply "marine-like" compounds for drug development.
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Chemical investigation of the marine fungus Ascochyta salicorniae led to the isolation of two new epimeric compounds, ascolactones A (1) and B (2), in addition to the structurally-related polyketides hyalopyrone (3), ascochitine (4), ascochital (5) and ascosalipyrone (6). The absolute configurations of the epimeric compounds 1 and 2 were assigned as (1R,9R) and (1S,9R), respectively, through simulation of the chiroptical properties using quantum-chemical CD calculations, and chiral GC-MS subsequent to oxidative cleavage (Baeyer-Villiger oxidation) of the side chain. In silico screening using the PASS software identified some of the A. salicorniae compounds (1-6) as potential inhibitors of protein phosphatases. Compound was found to inhibit the enzymatic activity of MPtpB with an IC(50) value of 11.5 microM.
The toxic effects of several species of fresh water cyanobacteria, notably Microcystis species and associated toxins, the microcystins, Anabaena species (anatoxin), Nodularia sp. (nodularin), and Cylindrospermopsis raciborskii (cylindrospermopsin), are well known. Little, however, is known about the effects of secondary metabolites other than alkaloids. Early life stage tests with zebrafish (Danio rerio) were used to detect bioactive properties of compounds released by healthy cyanobacteria (Fischerella ambigua), particularly on the early developmental stages of fish. This approach, using F. ambigua is probably most valuable as it shows the toxicity of healthy growing cyanobacteria. The effects of cyanobacterial secondary metabolites on the embryonic stages of fish are of considerable interest as many aquatic creatures, particularly fish, are unable to avoid the potential toxins that may be released by undesirable algal blooms or as a result of allelopathic effects. In the current study, the zebrafish (D. rerio) was used as a model experimental system to investigate the effects of ambigols A and C, tjipanazole D and C, 2,4-dichlorobenzoic acid, cell free culture media, and media extracts of a terrestrial/fresh water strain of the cyanobacterium F. ambigua on embryo development. Fish embryo tests performed with the cell free culture medium showed that after 3h of exposure to undiluted culture medium all fish embryos died. At a tenfold dilution the process of epiboly (formation of the gastrula) was retarded in all embryos, lesions were observed, and their general development was significantly arrested, finally followed by death. The same tests performed with extracts (dichloromethane, n-butanol, and residual cell free culture medium) of the cell free culture medium, ambigol A, ambigol C, 2,4-dichlorobenzoic acid and tjipanazole D showed only ambigol A to have an influence on zebrafish development at concentrations>or=1 mg/l (2.06 microM). After 55 h all embryos showed pectoral oedema, irregularly shaped fin folds, bent tails, and unusual circular neoplasms in the dorsal tail fin fold. Due to the high concentration of ambigol A used in this assay these effects were considered to be of minor importance when compared to those of the culture medium.
The marine environment is distinguished by unique groups of organisms being the source of a wide array of fascinating structures. The enormous biodiversity of marine habitats is mirrored by the molecular diversity of secondary metabolites found in marine animals, plants and microbes. The recognition that many marine invertebrates contain endo- and epibiotic microorganisms and that some invertebrate-derived natural products are structurally related to bacterial metabolites suggests a microbial origin for some of these compounds. Other marine natural products, however, are clearly located in invertebrate tissue and microbial involvement in the biosynthetic process seems unlikely. The complexity of associations in marine organisms, especially in sponges, bryozoans and tunicates, makes it extremely difficult to definitively state the biosynthetic source of many marine natural products or to deduce their ecological significance. Whereas many symbiotic marine microorganisms cannot be isolated and cultured, numerous epi- and endobiotic marine fungi produce novel secondary metabolites in laboratory cultures. The potent biological activity of many marine natural products is of relevance for their ecological function but is also the basis of their biomedical importance.
Two stereoisomers of ascolactone (A, B), natural products with two asymmetric carbon atoms, are isolated from the marine-derived fungus Ascochyta salicorniae. Although these compounds show virtually opposite CD spectra and [alpha]D, 1H- and 13C-NMR data exclude the presence of enantiomers and suggest ascolactone A and B to be epimeric lactones. By comparing the experimental CD spectra with those calculated employing time-dependent density functional theory (TDDFT), we elucidate the configuration at one of the asymmetric carbon atoms.
The fungus Emericella nidulans var. acristata was isolated as an endophyte from a Mediterranean green alga. Cultivation of this fungus yielded two new compounds, arugosins G (1) and H (2), together with the known metabolites 3-9. Arugosins (1-4) are benzophenone derivatives, biosynthetically related to the xanthones 5, 6, and 9. The indole alkaloid 7 displayed antitumor activity in a panel of 36 human tumor cell lines, exhibiting a mean IC(50) value of 5.5 microg/mL in an in vitro survival and proliferation assay. Furthermore, compounds 3 and 4 showed moderate antitumor activity toward individual tumor cell lines. None of compounds 1-8 exhibited any immunostimulatory activity assessed as the capacity to induce cytokines in PBMCs from healthy donors.
The effects of various Flustra foliacea metabolites on different types of human neuronal nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes were investigated. Whereas most of the compounds tested had a small blocking effect, one of them, deformylflustrabromine, selectively increased the current obtained in alpha4beta2 receptors when co-applied with acetylcholine (ACh). The current increase was reversible and concentration-dependent. This potentiating effect was still present at saturating concentrations of acetylcholine, and no changes in single-channel conductance or reversal potential were observed, thus suggesting a modification in the gating of alpha4beta2 receptors. Dwell time analysis of single channel records indicates that the mechanism of action of deformylflustrabromine could be both an increase of the opening rate constant and a decrease of the closing rate constant on alpha4beta2 receptors. Thus, deformylflustrabromine may constitute an excellent starting point for the future development of related agents able to potentiate human neuronal nicotinic receptor function.
The new natural products 3,5-bis(2,4-dichlorophenoxy)-2,6-dichlorophenol (ambigol C, 1), a highly chlorinated aromatic compound, and 2,4-dichlorobenzoic acid (2) were isolated from the terrestrial cyanobacterium Fischerella ambigua together with the known compounds ambigol A (3) and tjipanazole D (4). All structures were secured by extensive spectroscopic analysis (1D and 2D NMR, MS, UV, IR). Ambigol C has moderate activity against Trypanosoma rhodesiense.
The absolute configurations of fistularin-3, 11-epi-fistularin-3, and a related bis-oxazolidinone were determined by microscale hydrolysis followed by derivatization with 1-fluoro-2,4-dinitrophenyl-5-l-alaninamide. Samples of fistularin-3 from Verongid marine sponges collected in the Great Barrier Reef (Australia), Baía de Todos os Santos (Brazil), and the Key Largo, Florida (USA) varied in configuration at C11, a phenomenon that may be attributed to the involvement of stereochemically promiscuous hydroxylase enzymes. Variability in C11 configuration in fistularin-3 samples may have been overlooked in previously reported encounters due to the similarity of spectroscopic properties of fistularin-3 and 11-epi-fistularin-3 and their coelution under chromatographic conditions. Stereochemical heterogeneity at C11 in fistularin-3 samples suggests a possibility of a native biotransformation of suitable precursor in Verongid sponges by their associated microbial flora.
Chemical investigation of the deepwater sponge Macandrewia azorica, collected from the flanks of the Gettysburg and Ormonde Sea Mount, North Atlantic, from a depth of 600 m, has led to the isolation of a new sterol with an unusual side chain (1), along with S-methylergothioneine (2). The structures of compounds 1 and 2 were established by employing spectroscopic techniques (NMR, MS, UV, IR and polarimetry). This is the first report of metabolites of a sponge belonging to the genus Macandrewia.
Investigation of the methanolic extract of the Australian ascidian Atriolum robustum led to the isolation and characterization of five new amino acid derived structures (1-5). The structures were elucidated employing spectroscopic techniques (NMR, MS, UV, and IR). The absolute stereochemistry of 1 and 2 was established by chemical degradation, derivatization, and chiral GC-MS analysis. Structures 4 and 5 are complex nucleosides containing rare methylthioadenosine and methylsulfinyladenosine moieties, respectively. In radioligand binding studies the 5'-deoxy-5'-methylthioadenosine-2',3'-diester 4 exhibited affinity for A(1) and A(3) adenosine receptors with K(i) values below 10 microM. Its affinity was somewhat lower for A(2A) (K(i) = 17 microM) and much lower for A(2B) adenosine receptors. Analytical experiments using capillary electrophoresis showed that compound 4 was stable under the conditions of radioligand binding studies. Incubation with carboxylesterase resulted in slow hydrolysis of the adenosine derivative to 5'-deoxy-5'-methylthioadenosine (MTA), which was about 10-fold more potent at adenosine receptors than compound 4. Thus, the 2',3'-diester derivative 4 may act as a lipophilic prodrug of MTA in addition to its own adenosine receptor activity. GTP shift experiments indicated that the adenosine derivative was a partial agonist at A(1) adenosine receptors of rat brain cortical membranes. Compound 4 inhibited cAMP accumulation in Chinese hamster ovary (CHO) cell membranes recombinantly expressing the human A(3) adenosine receptor, thus indicating that the adenosine derivative also acted as a partial agonist at A(3)ARs. Homology models of the A(1) and the A(3) adenosine receptors in their putative active and inactive conformations were built and used for docking of the sterically demanding compound 4. It was found that this ligand fit well into the binding pockets of both receptor subtypes because of its highly flexible structure, although in somewhat different binding modes.
During the chemical investigation of a new species of soft coral belonging to the genus Sarcophyton, two novel cembranoid compounds with a 12Z double bond (1 and 2) were obtained. Determination of the double bond configurations was done using NMR spectroscopic data and the results of molecular modeling studies. Compound 3, one of several known compounds (3-5), was found to be cytotoxic toward an MCF7 tumor cell line.Additionally, we report the absolute stereochemistry of the cembrane sarcoglaucol-16-one (6), which was determined using the modified Mosher[prime or minute]s method.
Eukaryotic translation initiation factor (eIF-5A) is a highly conserved and essential protein that contains the unique amino acid hypusine. The first step in the post-translational biosynthesis of hypusine, the transfer of an aminobutyl moiety from the polyamine substrate spermidine to the -amino group of a specific lysine residue in the eIF-5A precursor, is catalyzed by the enzyme deoxyhypusine synthase. A cDNA encoding a protein homologous to eIF-5A was isolated by plaque hybridization from a cDNA library of Plasmodium falciparum. The cloned cDNA contains an open reading frame encoding a protein of 161 amino acids, which shares a high sequence identity with other eukaryotic eIF-5A sequences. A phylogenetic tree constructed with eIF-5A from P. falciparum and 16 other eIF-5A sequences of eukaryotic and archaeal origin reveals that plasmodial eIF-5A together with other apicomplexan eIF-5A show a higher degree of homology to plant proteins than to animal and fungal sequences. The plasmodial eIF-5A gene was expressed as a six-histidine tagged fusion protein in Escherichia coli. Radioactive incorporation studies with [1,8-3H] spermidine indicated that this protein can serve as a substrate for human deoxyhypusine synthase. Results of quantitative real-time PCR studies with synchronized erythrocytic stages of P. falciparum revealed no significant induction or downregulation but only some variation in the expression level of plasmodial eIF-5A in ring, trophozoite and schizont stage.
The marine fungus Apiospora montagnei was isolated from the inner tissue of the North Sea alga Polysiphonia violacea. Cultivation of this fungal strain led to the isolation of several new secondary metabolites, including the diterpene myrocin A (1) and the polyketide apiosporic acid (2). Furthermore the new monomethyl ester of 9-hydroxyhexylitaconic acid (3) and the (-)-enantiomer (4) of the known (+)-hexylitaconic acid were found together with the known (+)-epiepoxydon (5), (+)-epoxydon monoacetate, R-mellein, R-8-methoxymellein, 5-hydroxymethylfuran-2-carboxylic acid, and the xanthone derivative anomalin A. The structures were elucidated mainly by 1D and 2D NMR, MS, UV, and IR spectral data. Compound 5 exhibited significant cytoxicity against human cancer cell lines.
The variation of the brominated indole and diterpenoid content within single and different colonies of the bryozoan Flustra foliacea was investigated. The secondary metabolite profile and concentrations of individual components of F. foliacea samples were established using GC-MS. Samples from 17 different collecting sites were analyzed. The alkaloid and diterpene composition of F. foliacea varied greatly depending upon the site of collection. Investigation of F. foliacea samples from a single site (Helgoland, North Sea) over a period of time showed that the alkaloid and diterpenoid profile remained constant, however concentrations of individual components varied significantly. The alkaloid and diterpenoid composition of different segments of a single colony was found to be constant. Only small differences could be detected in the essential oil composition of different colonies and segments of single colonies of F. foliacea. Two of the F. foliacea alkaloids were found in the gastropods Hydrobia ulva and Gibbula cinerea, and one alkaloid in the common starfish Asteria rubens, all collected from the surface of the bryozoan.
Several brominated indole alkaloids and a diterpene (1-7) were isolated from the dichloromethane extract of the North Sea Bryozoan Flustra foliacea. Alkaloid 4 is a new natural product, whose structure was elucidated by interpretation of spectroscopic data (NMR, mass, UV, and IR). All compounds were tested for their in vitro affinity towards the alpha4beta2* and alpha7* subtype of the neuronal nicotinic acetylcholine receptor (nAChR) using radioligand binding assays. Deformylflustrabromine (3) and deformylflustrabromine B (4) were shown to have affinities in the lower micromolar range for nAChRs, differing in their subtype preference.