ABSTRACT
Epoxyphomalins A (1) and B (2) are highly potent cytotoxic fungal metabolites. During the course of purifying larger quantities of 1 and 2 from Paraconiothyrium sp. fermentation extracts, three new epoxyphomalins (3-5) were isolated and characterized, showing modifications to the oxidation pattern of the cyclohexene moiety or of C-9 of the decalin system. IC(50) values for cytotoxicity against a panel of 36 human tumor cell lines were determined for all new compounds. Compound 4 was found to be cytotoxic particularly toward prostate PC3M (IC(50) = 0.72 µM) and bladder BXF 1218 L (IC(50) = 1.43 µM) cancer cell lines. In addition, inhibition of chymotrypsin-, caspase-, and trypsin-like activity of purified 20S proteasomes was determined for epoxyphomalins A (1) and B (2). The results indicate that compounds 1 and 2 exert their cytotoxic effect through potent inhibition of the 20S proteasome.
Subject(s)
Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Ascomycota/chemistry , Macrolides/isolation & purification , Macrolides/pharmacology , Proteasome Inhibitors , Antineoplastic Agents/chemistry , Caspase Inhibitors , Drug Screening Assays, Antitumor , Humans , Macrolides/chemistry , Male , Marine Biology , Molecular Structure , Nuclear Magnetic Resonance, BiomolecularABSTRACT
Within a project focusing on the chemopreventive potential of algal phenols, two phloroglucinol derivatives, belonging to the class of fucophlorethols, and the known fucotriphlorethol A were obtained from the ethanolic extract of the brown alga Fucus vesiculosus L. The compounds trifucodiphlorethol A and trifucotriphlorethol A are composed of six and seven units of phloroglucinol, respectively. The compounds were examined for their cancer chemopreventive potential, in comparison with the monomer phloroglucinol. Trifucodiphlorethol A, trifucotriphlorethol A as well as fucotriphlorethol A were identified as strong radical scavengers, with IC(50) values for scavenging of 1,1-diphenyl-2 picrylhydrazyl radicals (DPPH) in the range of 10.0-14.4 microg/ml. All three compounds potently scavenged peroxyl radicals in the oxygen radical absorbance capacity (ORAC) assay. In addition, the compounds were shown to inhibit cytochrome P450 1A activity with IC(50) values in the range of 17.9-33 microg/ml, and aromatase (Cyp19) activity with IC(50) values in the range of 1.2-5.6 microg/ml.
Subject(s)
Antioxidants/pharmacology , Aromatase Inhibitors/pharmacology , Biphenyl Compounds/pharmacology , Cytochrome P-450 Enzyme Inhibitors , Fucus/chemistry , Phenyl Ethers/pharmacology , Phloroglucinol/pharmacology , Terphenyl Compounds/pharmacology , Animals , Antineoplastic Agents, Phytogenic/isolation & purification , Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Agents, Phytogenic/therapeutic use , Antioxidants/isolation & purification , Antioxidants/therapeutic use , Aromatase Inhibitors/isolation & purification , Aromatase Inhibitors/therapeutic use , Biphenyl Compounds/isolation & purification , Biphenyl Compounds/therapeutic use , Cell Line, Tumor , Humans , Inhibitory Concentration 50 , Mice , Neoplasms/drug therapy , Phenyl Ethers/isolation & purification , Phenyl Ethers/therapeutic use , Phloroglucinol/analogs & derivatives , Phloroglucinol/therapeutic use , Picrates , Plant Extracts/chemistry , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Terphenyl Compounds/isolation & purification , Terphenyl Compounds/therapeutic useABSTRACT
Chemical investigation of a strain of the marine-derived fungus Phoma sp. has led to the discovery of epoxyphomalin A (1) and B (2), two new prenylated polyketides with unusual structural features. Epoxyphomalin A (1) showed superior cytotoxicity at nanomolar concentrations toward 12 of a panel of 36 human tumor cell lines. In COMPARE analyses, the observed cytotoxic selectivity pattern of 1 did not correlate with those of reference anticancer agents with known mechanisms of action.
Subject(s)
Antineoplastic Agents , Ascomycota/chemistry , Macrolides , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Drug Screening Assays, Antitumor , Humans , Macrolides/chemistry , Macrolides/isolation & purification , Macrolides/pharmacology , Marine Biology , Porifera/microbiologyABSTRACT
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.
Subject(s)
Antineoplastic Agents/isolation & purification , Glycolipids/isolation & purification , Myxococcus/chemistry , Rhamnose/analogs & derivatives , Rhamnose/isolation & purification , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Bacillus megaterium/drug effects , Chlorella/drug effects , Drug Screening Assays, Antitumor , Escherichia coli/drug effects , Eurotium/drug effects , Fatty Acids/genetics , Gas Chromatography-Mass Spectrometry , Glycolipids/chemistry , Glycolipids/pharmacology , Microbial Sensitivity Tests , Molecular Structure , Plasmodium falciparum/drug effects , Pseudomonas putida/drug effects , Quorum Sensing , Rhamnose/chemistry , Rhamnose/pharmacologyABSTRACT
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.
Subject(s)
Myxococcales/metabolism , Pyrones/chemistry , Drug Design , Mass Spectrometry , Models, Molecular , Pyrones/metabolism , Pyrones/pharmacologySubject(s)
Ascomycota/chemistry , Chromones/chemistry , Neoplasms/drug therapy , Neoplasms/prevention & control , Animals , Chromones/pharmacology , Circular Dichroism , Cytochrome P-450 CYP1A1/antagonists & inhibitors , Cytochrome P-450 CYP1A1/drug effects , Dose-Response Relationship, Drug , Magnetic Resonance Spectroscopy , Molecular StructureABSTRACT
Investigations of the marine-derived fungus Monodictys putredinis led to the isolation of two novel dimeric chromanones (1, 2) that consist of two uniquely modified xanthone-derived units. The structures were elucidated by extensive spectroscopic measurements including NOE experiments and CD analysis to deduce the configuration. The compounds (1, 2) were examined for their cancer chemopreventive potential and shown to inhibit cytochrome P450 1A activity with IC(50) values of 5.3 and 7.5 µM, respectively. In addition, both compounds displayed moderate activity as inducers of NAD(P)H:quinone reductase (QR) in cultured mouse Hepa 1c1c7 cells, with CD values (concentration required to double the specific activity of QR) of 22.1 and 24.8 µM, respectively. Compound 1 was slightly less potent than compound 2 in inhibiting aromatase activity, with IC(50) values of 24.4 and 16.5 µM.
Subject(s)
Anticarcinogenic Agents/isolation & purification , Aromatase Inhibitors/isolation & purification , Ascomycota/chemistry , Chromones/isolation & purification , Xanthones/isolation & purification , Animals , Anticarcinogenic Agents/chemistry , Anticarcinogenic Agents/pharmacology , Aromatase Inhibitors/chemistry , Aromatase Inhibitors/pharmacology , Chlorophyta/microbiology , Chromones/chemistry , Chromones/pharmacology , Enzyme Induction/drug effects , Inhibitory Concentration 50 , Marine Biology , Mice , Molecular Structure , NAD(P)H Dehydrogenase (Quinone)/biosynthesis , NAD(P)H Dehydrogenase (Quinone)/drug effects , Spain , Xanthones/chemistry , Xanthones/pharmacologyABSTRACT
Investigations of the marine-derived fungus Chaetomium sp. led to the isolation of the new natural products chaetoxanthones A, B, and C (1-3). Compounds 1 and 2 are substituted with a dioxane/tetrahydropyran moiety rarely found in natural products. Compound 3 was identified as a chlorinated xanthone substituted with a tetrahydropyran ring. The configurational analysis of these compounds employed CD spectroscopy, modified Mosher's method, and selective NOE gradient measurements. Compound 2 showed selective activity against Plasmodium falciparum with an IC50 value of 0.5 microg/mL without being cytotoxic toward cultured eukaryotic cells. Compound 3 displayed a moderate activity against Trypanosoma cruzi with an IC50 value of 1.5 microg/mL.
Subject(s)
Antiprotozoal Agents/isolation & purification , Antiprotozoal Agents/pharmacology , Xanthones/isolation & purification , Xanthones/pharmacology , Animals , Antiprotozoal Agents/chemistry , Bacillus megaterium/drug effects , Chaetomium , Chlorella/drug effects , Drug Screening Assays, Antitumor , Escherichia coli/drug effects , Leishmania donovani/drug effects , Marine Biology , Microbial Sensitivity Tests , Models, Molecular , Parasitic Sensitivity Tests , Plasmodium falciparum/drug effects , Rats , Trypanosoma cruzi/drug effects , Xanthones/chemistryABSTRACT
A new cytotoxic bastadin, bastadin 24 ( 1), and the previously reported bastadins 4, 5, 6, 7, 12, 13, and 21 ( 2- 8) were isolated from a polar extract of the Australian marine sponge Ianthella quadrangulata. The planar structure of bastadin 24 ( 1) was elucidated as the 25-hydroxy derivative of bastadin 6 ( 4) by employing spectroscopic techniques (NMR, MS, UV, and IR). All isolated bastadins were evaluated for their cytotoxicity toward a panel of 36 human tumor cell lines and were found to be moderately cytotoxic. Bastadin 24 ( 1) exhibited selective cytotoxic activity toward five of the 36 investigated tumor cell lines. Bastadins 7 ( 5) and 12 ( 6) significantly inhibited the serum + hEGF-induced (human epithelial growth factor) tubular formation of human umbilical vein endothelial cells (HUVEC) at a concentration of 1 mug/mL.
Subject(s)
Peptides, Cyclic/isolation & purification , Phenyl Ethers/isolation & purification , Porifera/chemistry , Angiogenesis Inhibitors/blood , Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/isolation & purification , Angiogenesis Inhibitors/pharmacology , Animals , Australia , Drug Screening Assays, Antitumor , Endothelial Cells/drug effects , Epidermal Growth Factor/metabolism , Halogenated Diphenyl Ethers , Humans , Inhibitory Concentration 50 , Molecular Structure , Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology , Phenyl Ethers/blood , Phenyl Ethers/chemistry , Phenyl Ethers/pharmacology , Umbilical Veins/cytology , Umbilical Veins/drug effectsABSTRACT
The investigation of the marine-derived fungi Acremonium sp. and Nodulisporium sp. led to the isolation of the new natural products acremonisol A ( 1) and (3 R)-7-hydroxy-5-methylmellein ( 2). Both fungi are endophytes of marine algae. Compounds 1 and 2 are biosynthetically related by both being aromatic pentaketides belonging to the dihydroisocoumarins. All structures were elucidated by extensive spectroscopic measurements.
Subject(s)
Acremonium/chemistry , Ascomycota/chemistry , Chlorobenzoates/isolation & purification , Isocoumarins/isolation & purification , Bacillus megaterium/drug effects , Chlorobenzoates/chemistry , Chlorobenzoates/pharmacology , Drug Screening Assays, Antitumor , Escherichia coli/drug effects , Fungi/drug effects , Isocoumarins/chemistry , Isocoumarins/pharmacology , Marine Biology , Microbial Sensitivity Tests , Molecular StructureABSTRACT
Three new iantherans, iso-iantheran A (1), 8-carboxy-iso-iantheran A (2), and iso-iantheran B (4) were isolated together with two further new brominated tyrosine-derived metabolites 5 and 6 from the polar extract of the Australian marine sponge Ianthella quadrangulata. Structures were elucidated on the basis of extensive spectral analysis. The dimeric benzofuran skeleton including a 2,3-dihydroxy-1,3-butadiene disulfate moiety found in 1, 2, and 4 is a unique feature of iantherans and to date only described for iantherans A and B. Iso-iantheran A (1) and 8-carboxy-iso-iantheran A (2) exhibited agonist activity at P2Y11 receptors with EC50 values of 1.29 muM and 0.48 muM, respectively. Compound 2 showed some selectivity for P2Y11 over P2Y1 and P2Y2 receptors. Compounds 1 and 2 represent a new structural type for the development of P2Y11 receptor agonists.
Subject(s)
Benzofurans/isolation & purification , Porifera/chemistry , Purinergic P2 Receptor Agonists , Sulfuric Acid Esters/isolation & purification , Tyrosine/analogs & derivatives , Tyrosine/isolation & purification , Animals , Benzofurans/chemistry , Benzofurans/pharmacology , Calcium/metabolism , Cell Line, Tumor , Humans , Ligands , Models, Molecular , Receptors, Purinergic P2 , Structure-Activity Relationship , Sulfuric Acid Esters/chemistry , Sulfuric Acid Esters/pharmacology , Tyrosine/chemistry , Tyrosine/pharmacologyABSTRACT
Our study focused on a Mesorhizobium sp. that is phylogenetically affiliated by 16S rRNA gene sequence to other marine and saline bacteria of this genus. Liquid chromatography-mass spectrometry investigations of the extract obtained from solid-phase extraction of cultures of this bacterium indicated the presence of several N-acyl homoserine lactones (AHLs), with chain lengths of C(10) to C(16). Chromatographic separation of the active bacterial extract yielded extraordinarily large amounts of two unprecedented acylated homoserine lactones, 5-cis-3-oxo-C(12)-homoserine lactone (5-cis-3-oxo-C(12)-HSL) (compound 1) and 5-cis-C(12)-HSL (compound 2). Quorum-sensing activity of compounds 1 and 2 was shown in two different biosensor systems [Escherichia coli MT102(pSB403) and Pseudomonas putida F117(pKR-C12)]. Furthermore, it was shown that both compounds can restore protease and pyoverdin production of an AHL-deficient Pseudomonas aeruginosa PAO1 lasI rhlI double mutant, suggesting that these signal molecules maybe used for intergenus signaling. In conclusion, these data indicate that the quorum-sensing activity of compounds 1 and 2 is modulated by the chain length and functional groups of the acyl moiety. Additionally, compound 1 showed antibacterial and cytotoxic activities.
Subject(s)
Alphaproteobacteria/isolation & purification , Alphaproteobacteria/metabolism , Porifera/microbiology , Alphaproteobacteria/classification , Alphaproteobacteria/genetics , Animals , Antineoplastic Agents/pharmacology , Bacillus/drug effects , Bacterial Proteins/biosynthesis , Bacterial Proteins/genetics , Chromatography, Liquid , DNA, Bacterial/chemistry , DNA, Bacterial/genetics , DNA, Ribosomal/chemistry , DNA, Ribosomal/genetics , Escherichia coli/drug effects , Gene Deletion , Genes, rRNA , Ligases/genetics , Mass Spectrometry , Molecular Sequence Data , Norway , Phylogeny , Pseudomonas aeruginosa/drug effects , Pseudomonas putida/drug effects , Quorum Sensing/drug effects , RNA, Bacterial/genetics , RNA, Ribosomal, 16S/genetics , Sequence Analysis, DNA , Sequence Homology, Nucleic Acid , Transcription Factors/geneticsABSTRACT
Investigation of the secondary metabolites of the marine-derived fungus Spicellum roseum yielded two new cyclohexadepsipeptides, spicellamide A (1) and spicellamide B (2). The structures of 1 and 2 were determined based on extensive evaluations of NMR and MS data. The absolute configuration was deduced after hydrolysis using Marfey's method, chiral chromatography, as well as NOESY and modeling data.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Depsipeptides/pharmacology , Fungi , Phytotherapy , Animals , Antineoplastic Agents, Phytogenic/chemistry , Cell Line, Tumor/drug effects , Depsipeptides/chemistry , Humans , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular Structure , Neuroblastoma/pathology , RatsABSTRACT
Investigation of the fungal strain Monodictys putredinis isolated from the inner tissue of a marine green alga led to the isolation of four new monomeric xanthones and a benzophenone. All structures were elucidated by extensive spectroscopic measurements. The relative configuration of compound 1 was determined by X-ray crystal structure analysis, while for 2 and 3 configurations were confirmed by NOE experiments. Absolute configurations for compounds 1-3 were deduced by comparing experimental circular dichroism spectroscopic data with those calculated employing quantum-chemical time-dependent density functional theory (TDDFT). The compounds were examined for their cancer chemopreventive potential. Xanthone 2 was shown to inhibit cytochrome P450 1A activity with an IC50 value of 3.0 microM. Compounds 2 and 3 displayed moderate activity as inducers of NAD(P)H:quinone reductase (QR) in cultured mouse Hepa 1c1c7 cells, with CD values (concentration required to double the specific activity of QR) of 12.0 and 12.8 microM, respectively. Compound 3 showed weak inhibition of aromatase activity.
Subject(s)
Anticarcinogenic Agents , Aromatase Inhibitors , Ascomycota/chemistry , Xanthones , Anticarcinogenic Agents/chemistry , Anticarcinogenic Agents/isolation & purification , Anticarcinogenic Agents/pharmacology , Aromatase Inhibitors/chemistry , Aromatase Inhibitors/isolation & purification , Aromatase Inhibitors/pharmacology , Crystallography, X-Ray , Inhibitory Concentration 50 , Marine Biology , Molecular Conformation , Molecular Structure , NAD(P)H Dehydrogenase (Quinone)/biosynthesis , Xanthones/chemistry , Xanthones/isolation & purification , Xanthones/pharmacologyABSTRACT
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].
Subject(s)
Ascomycota/chemistry , Ethers, Cyclic/chemistry , Spiro Compounds/chemistry , Ethers, Cyclic/isolation & purification , Magnetic Resonance Spectroscopy/methods , Magnetic Resonance Spectroscopy/standards , Models, Molecular , Molecular Conformation , Reference Standards , Spiro Compounds/isolation & purification , StereoisomerismABSTRACT
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.
Subject(s)
Bacterial Proteins/antagonists & inhibitors , Bacterial Proteins/chemistry , Cyanobacteria/chemistry , Mycobacterium tuberculosis/enzymology , Peptides, Cyclic/chemistry , Protein Tyrosine Phosphatases/antagonists & inhibitors , Protein Tyrosine Phosphatases/chemistry , Animals , Molecular Structure , Peptides, Cyclic/isolation & purification , Structure-Activity Relationship , Theonella/chemistryABSTRACT
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.
Subject(s)
Fungi/chemistry , Heterocyclic Compounds, 3-Ring/isolation & purification , Phenols/isolation & purification , Bacillus megaterium/drug effects , Chlorella/drug effects , Chlorophyta , Cytokines/drug effects , Drug Screening Assays, Antitumor , Escherichia coli/drug effects , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , Inhibitory Concentration 50 , Marine Biology , Mediterranean Sea , Phenols/chemistry , Phenols/pharmacology , Tumor Cells, Cultured , Xanthones/chemistry , Xanthones/isolation & purification , Xanthones/pharmacologyABSTRACT
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.
Subject(s)
Ascomycota/chemistry , Enzyme Inhibitors/isolation & purification , Enzyme Inhibitors/pharmacology , Macrolides/isolation & purification , Macrolides/pharmacology , Phosphoprotein Phosphatases/antagonists & inhibitors , Circular Dichroism , Enzyme Inhibitors/chemistry , Macrolides/chemistry , Nuclear Magnetic Resonance, BiomolecularABSTRACT
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.