ABSTRACT
Rare actinomycetes represent an underexploited source of new bioactive compounds. Here, we report the use of a targeted metabologenomic approach to identify piperazyl compounds in the rare actinomycete Lentzea flaviverrucosa DSM 44664. These efforts to identify molecules that incorporate piperazate building blocks resulted in the discovery and structural elucidation of two dimeric biaryl-cyclohexapeptides, petrichorins A and B. Petrichorin B is a symmetric homodimer similar to the known compound chloptosin, but petrichorin A is unique among known piperazyl cyclopeptides because it is an asymmetric heterodimer. Due to the structural complexity of petrichorin A, solving its structure required a combination of several standard chemical methods plus in silico modeling, strain mutagenesis, and solving the structure of its biosynthetic intermediate petrichorin C for confident assignment. Furthermore, we found that the piperazyl cyclopeptides comprising each half of the petrichorin A heterodimer are made via two distinct nonribosomal peptide synthetase (NRPS) assembly lines, and the responsible NRPS enzymes are encoded within a contiguous biosynthetic supercluster on the L. flaviverrucosa chromosome. Requiring promiscuous cytochrome p450 crosslinking events for asymmetric and symmetric biaryl production, petrichorins A and B exhibited potent in vitro activity against A2780 human ovarian cancer, HT1080 fibrosarcoma, PC3 human prostate cancer, and Jurkat human T lymphocyte cell lines with IC50 values at low nM levels. Cyclic piperazyl peptides and their crosslinked derivatives are interesting drug leads, and our findings highlight the potential for heterodimeric bicyclic peptides such as petrichorin A for inclusion in future pharmaceutical design and discovery programs.
Subject(s)
Actinobacteria , Actinomycetales , Streptomyces , Actinobacteria/genetics , Actinomycetales/genetics , Multigene Family , Peptides, Cyclic/genetics , Streptomyces/geneticsABSTRACT
The structure of petrichorin C1 (4) converted from petrichorin C (3) was determined using NMR spectroscopy and X-ray crystallography. The chemical stability of petrichorins A and C (1 and 3) was investigated by NMR spectroscopy, X-ray crystallography, and calculations.
Subject(s)
Models, Molecular , Crystallography, X-Ray , Magnetic Resonance Spectroscopy/methodsABSTRACT
The study of a Hawaiian volcanic soil-associated fungal strain Penicillium herquei FT729 led to the isolation of one unprecedented benzoquinone-chromanone, herqueilenone A (1) and two phenalenone derivatives (2 and 3). Their structures were determined through extensive analysis of NMR spectroscopic data and gauge-including atomic orbital (GIAO) NMR chemical shifts and ECD calculations. Herqueilenone A (1) contains a chroman-4-one core flanked by a tetrahydrofuran and a benzoquinone with an acetophenone moiety. Plausible pathways for the biosynthesis of 1-3 are proposed. Compounds 2 and 3 inhibited IDO1 activity with IC50 values of 14.38 and 13.69 µM, respectively. Compounds 2 and 3 also demonstrated a protective effect against acetaldehyde-induced damage in PC-12 cells.
Subject(s)
Enzyme Inhibitors/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Penicillium/chemistry , Phenalenes/pharmacology , Acetaldehyde/antagonists & inhibitors , Acetaldehyde/pharmacology , Animals , Cell Survival/drug effects , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/isolation & purification , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Microbial Sensitivity Tests , Molecular Structure , PC12 Cells , Phenalenes/chemistry , Phenalenes/isolation & purification , Rats , Structure-Activity RelationshipABSTRACT
A new polyketide containing the benzoisoquinoline-9-one moiety, peyronetide A (1), and three other new derivatives peyronetides Bâ»D (2â»4), as well as one known compound (5) were purified from the cultured broth of the endophytic fungus Peyronellaea sp. FT431, which was isolated from the Hawaiian indigenous plant, Verbena sp. The structures of the new compounds were determined through the analysis of HRMS and NMR spectroscopic data. Compounds 1, 2, and 5 showed cytotoxic activities against TK-10 (human kidney adenocarcinoma cells), cisplatin sensitive A2780S (human ovarian carcinoma cells), and cisplatin resistant A2780CisR cell lines, with IC50 values between 6.7 to 29.2 µM.
Subject(s)
Ascomycota/chemistry , Cell Proliferation/drug effects , Isoquinolines/pharmacology , Neoplasms/drug therapy , Cell Line, Tumor , Cisplatin/adverse effects , Drug Resistance, Neoplasm/drug effects , Endophytes/chemistry , Hawaii , Humans , Inhibitory Concentration 50 , Isoquinolines/chemistry , Isoquinolines/isolation & purification , Magnetic Resonance Spectroscopy , Molecular StructureABSTRACT
A new secondary metabolite verbenanone (1) with a unique (4aS,8aS)-octahydro-5H-chromen-5-one moiety has been obtained from the endophytic fungus FT431, which was isolated from the native Hawaiian plant Verbena sp. The structure of compound 1 was characterized based on NMR and MS spectroscopic analysis. The absolute configuration (AC) of compound 1 was determined by Mosher acids. Compound 1 was tested against A2780 and A2780cisR, but it was inactive.
ABSTRACT
A new N-methoxypyridone analog (1), together with four known compounds, was isolated from the co-culture of Hawaiian endophytic fungi Camporesia sambuci FT1061 and Epicoccum sorghinum FT1062. The structure of the new compound was elucidated as 11S-hydroxy-1-methoxyfusaricide (1) by extensive spectroscopic analysis and comparison with the literature. The absolute configuration of 1 was determined by comparison with the experimental and calculated ECD spectra. The absolute configuration of compound 3 was investigated and renamed as (+)-epipyridone by comparison of the optical rotation and CD spectrum with those of 1. The other known compounds were identified as epicoccarine B (2), D8646-2-6 (4), and iso-D8646-2-6 (5). Compounds 4 and 5 showed modest inhibitory activity towards pathogenic fungi. Epicoccarine B (2) inhibited A2780 and TK-10 with an IC50 value of 22 µM.
Subject(s)
Ascomycota/chemistry , Benzopyrans/chemistry , Endophytes/chemistry , Pyridones/chemistry , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/isolation & purification , Antifungal Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Benzopyrans/isolation & purification , Benzopyrans/pharmacology , Cell Line , Cell Proliferation/drug effects , Coculture Techniques , Hawaii , Pyridones/isolation & purification , Pyridones/pharmacology , Pyrrolidinones/chemistry , Pyrrolidinones/isolation & purification , Pyrrolidinones/pharmacologyABSTRACT
The potential anti-tumor agent wentilactones were produced by a newly isolated marine fungus Aspergillus dimorphicus. This fungus was derived from deep-sea sediment and identified by polyphasic approach, combining phenotypic, molecular, and extrolite profiles. However, wentilactone production was detected only under static cultures with very low yields. In order to improve wentilactone production, culture conditions were optimized using the response surface methodology. Under the optimal static fermentation conditions, the experimental values were closely consistent with the prediction model. The yields of wentilactone A and B were increased about 11-fold to 13.4 and 6.5 mg/L, respectively. The result was further verified by fermentation scale-up for wentilactone production. Moreover, some small-molecule elicitors were found to have capacity of stimulating wentilactone production. To our knowledge, this is first report of optimized production of tetranorlabdane diterpenoids by a deep-sea derived marine fungus. The present study might be valuable for efficient production of wentilactones and fundamental investigation of the anti-tumor mechanism of norditerpenoids.
Subject(s)
Antineoplastic Agents/isolation & purification , Aspergillus/metabolism , Geologic Sediments/microbiology , Heterocyclic Compounds, 4 or More Rings/isolation & purification , Aspergillus/isolation & purification , Culture Media , FermentationABSTRACT
Three new cyclohexadepsipeptides of the isaridin class including isaridin G (1), desmethylisaridin G (2), and desmethylisaridin C1 (3), along with three related known metabolites (4-6), were isolated and identified from the marine bryozoan-derived fungus Beauveria felina EN-135. The structures of these compounds were elucidated on the basis of extensive spectroscopic analysis, and the structures and absolute configurations of compounds 1-3 were confirmed by single-crystal X-ray diffraction analysis. The crystal structures showed the presence of ß-turns for the Tyr(3)/N-Me-Val(4) and Phe(3)/N-Me-Val(4) amide bonds in compounds 2 and 3, respectively, in the cis conformations, which were opposite other reported isaridins. The conformations of the HMPA(1)-Pro(2) amide bond in compound 2 are different in the solution and in the crystal structures, which showed trans and cis geometries, respectively, while compounds 1 and 3 do not exhibit this phenomenon. Each of the isolated compounds was evaluated for antimicrobial activity and brine shrimp lethality. Compound 3 exhibited antibacterial activity against E. coli with an MIC value of 8 µg/mL.
Subject(s)
Anti-Bacterial Agents/isolation & purification , Anti-Bacterial Agents/pharmacology , Beauveria/chemistry , Depsipeptides/isolation & purification , Depsipeptides/pharmacology , Animals , Anti-Bacterial Agents/chemistry , Artemia/drug effects , Crystallography, X-Ray , Depsipeptides/chemistry , Edwardsiella tarda/drug effects , Escherichia coli/drug effects , Marine Biology , Microbial Sensitivity Tests , Molecular Conformation , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Pseudomonas aeruginosa/drug effects , Staphylococcus aureus/drug effects , Stereoisomerism , Vibrio/drug effectsABSTRACT
Bioassay-guided fractionation of a culture extract of Beauveria felina EN-135, an entomopathogenic fungus isolated from a marine bryozoan, led to the isolation of a new cyclodepsipeptide, iso-isariin D (1); two new O-containing heterocyclic compounds that we have named felinones A and B (2 and 3); and four known cyclodepsipeptides (4-7). The structures were elucidated via spectroscopic analysis, and the absolute configurations of 1 and 2 were determined using single-crystal X-ray diffraction and CD, respectively. All isolated compounds were evaluated for antimicrobial activity and brine-shrimp (Artemia salina) lethality.
Subject(s)
Beauveria/chemistry , Depsipeptides/chemistry , Heterocyclic Compounds/chemistry , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/isolation & purification , Anti-Bacterial Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Artemia , Bacteria/drug effects , Depsipeptides/isolation & purification , Depsipeptides/pharmacology , Drug Screening Assays, Antitumor , Fungi/drug effects , Heterocyclic Compounds/isolation & purification , Heterocyclic Compounds/pharmacology , Microbial Sensitivity Tests , Models, Molecular , Molecular ConformationABSTRACT
Three new indolediketopiperazine peroxides, namely, 24-hydroxyverruculogen (1), 26-hydroxyverruculogen (2), and 13-O-prenyl-26-hydroxyverruculogen (3), along with four known homologues (4-7), were isolated and identified from the culture extract of the marine sediment-derived fungus Penicillium brefeldianum SD-273. Their structures were determined based on the extensive spectroscopic analysis and compound 1 was confirmed by X-ray crystallographic analysis. The absolute configuration of compounds 1-3 was determined using chiral HPLC analysis of their acidic hydrolysates. Each of the isolated compounds was evaluated for antibacterial and cytotoxic activity as well as brine shrimp (Artemia salina) lethality.
Subject(s)
Diketopiperazines/pharmacology , Indoles/pharmacology , Penicillium/metabolism , Peroxides/pharmacology , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/isolation & purification , Anti-Bacterial Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Artemia/drug effects , Cell Line, Tumor , Chromatography, High Pressure Liquid , Crystallography, X-Ray , Diketopiperazines/chemistry , Diketopiperazines/isolation & purification , Geologic Sediments/microbiology , Humans , Indoles/chemistry , Indoles/isolation & purification , Peroxides/chemistry , Peroxides/isolation & purification , Prenylation , Spectrum Analysis , Toxicity Tests/methodsABSTRACT
Six new 4-phenyl-3,4-dihydroquinolone derivatives (1-6) along with the related aflaquinolone A (7) were isolated and identified from the cultures of Aspergillus nidulans MA-143, an endophytic fungus obtained from the fresh leaves of the marine mangrove plant Rhizophora stylosa. Their structures including absolute configurations were determined by spectroscopic analysis and electronic circular dichroism experiments, and the structure of compound 1 was confirmed by single-crystal X-ray crystallographic analysis. In bioscreening experiments, none of the isolated compounds showed potent antibacterial or cytotoxic activity. However, compounds 2, 3, and 7 exhibited lethality against brine shrimp (Artemia salina), with LD50 values of 7.1, 4.5, and 5.5 µM, respectively.
Subject(s)
Aspergillus nidulans/chemistry , Quinolones/isolation & purification , Rhizophoraceae/microbiology , Animals , Artemia/drug effects , Circular Dichroism , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Escherichia coli/drug effects , Female , HL-60 Cells , Humans , K562 Cells , Microbial Sensitivity Tests , Molecular Conformation , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Plant Leaves/microbiology , Quinolones/chemistry , Quinolones/pharmacology , Staphylococcus aureus/drug effectsABSTRACT
Sumalarins A-C (1-3), the new and rare examples of sulfur-containing curvularin derivatives, along with three known analogues (4-6), were isolated and identified from the cytotoxic extract of Penicillium sumatrense MA-92, a fungus obtained from the rhizosphere of the mangrove Lumnitzera racemosa . Their structures were established by detailed interpretation of NMR and MS data, and compound 1 was confirmed by X-ray crystallographic analysis. Compounds 1-3 and 5 showed potent cytotoxicity against some of the tested tumor cell lines. Sulfur substitution at C-11 or a double bond at C-10 significantly increased the cytotoxic activities of the curvularin analogues.
Subject(s)
Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Combretaceae/microbiology , Macrolides/isolation & purification , Macrolides/pharmacology , Penicillium/chemistry , Sulfur/analysis , Zearalenone/analogs & derivatives , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/isolation & purification , Antineoplastic Agents/chemistry , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Humans , Macrolides/chemistry , Molecular Conformation , Molecular Structure , Structure-Activity Relationship , Zearalenone/chemistry , Zearalenone/isolation & purification , Zearalenone/pharmacologyABSTRACT
Two new secondary metabolites, namely, pinodiketopiperazine A (1) and 6,7-dihydroxy-3-methoxy-3-methylphthalide (2), along with alternariol 2,4-dimethyl ether (3) and L-5-oxoproline methyl ester (4), which were isolated from a natural source for the first time but have been previously synthesized, were characterized from the marine sediment-derived fungus Penicillium pinophilum SD-272. In addition, six known metabolites (5-10) were also identified. Their structures were elucidated by analysis of the NMR and mass spectroscopic data. The absolute configuration of compound 1 was determined by experimental and calculated ECD spectra. Compound 2 displayed potent brine shrimp (Artemia salina) lethality with LD50 11.2 µM.
Subject(s)
Anti-Bacterial Agents/pharmacology , Geologic Sediments/microbiology , Penicillium/metabolism , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/isolation & purification , Artemia/drug effects , Lethal Dose 50 , Magnetic Resonance Spectroscopy , Mass Spectrometry , Toxicity Tests/methodsABSTRACT
Five new anthranilic acid derivatives, penipacids A-E (1-5), together with one known analogue (6), which was previously synthesized, were characterized from the ethyl acetate extract of the marine sediment-derived fungus Penicillium paneum SD-44. Their structures were elucidated mainly by extensive NMR spectroscopic and mass spectrometric analysis. The cytotoxicity and antimicrobial activity of the isolated compounds were evaluated. Compounds 1, and 5 exhibited inhibitory activity against human colon cancer RKO cell line, while compound 6 displayed cytotoxic activity against Hela cell line.
Subject(s)
Anti-Infective Agents/pharmacology , Antineoplastic Agents/pharmacology , Penicillium/chemistry , ortho-Aminobenzoates/pharmacology , Anti-Infective Agents/chemistry , Anti-Infective Agents/isolation & purification , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Cell Line, Tumor , Colonic Neoplasms/drug therapy , Colonic Neoplasms/pathology , Geologic Sediments , HeLa Cells , Humans , Magnetic Resonance Spectroscopy , Mass Spectrometry , Mycophenolic Acid/analogs & derivatives , Mycophenolic Acid/chemistry , Mycophenolic Acid/isolation & purification , Mycophenolic Acid/pharmacology , ortho-Aminobenzoates/chemistry , ortho-Aminobenzoates/isolation & purificationABSTRACT
Four new quinazolinone alkaloids, namely, aniquinazolines A-D (1-4), were isolated and identified from the culture of Aspergillus nidulans MA-143, an endophytic fungus obtained from the leaves of marine mangrove plant Rhizophora stylosa. The structures of the new compounds were elucidated by spectroscopic analysis, and their absolute configurations were determined on the basis of chiral HPLC analysis of the acidic hydrolysates. The structure for 1 was confirmed by single-crystal X-ray diffraction analysis. All these compounds were examined for antibacterial and cytotoxic activity as well as brine shrimp (Artemia salina) lethality.
Subject(s)
Alkaloids/chemistry , Alkaloids/pharmacology , Aspergillus nidulans/chemistry , Quinazolinones/chemistry , Quinazolinones/pharmacology , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Artemia/drug effects , Biological Factors/chemistry , Biological Factors/pharmacology , Crystallography, X-Ray/methods , Molecular Structure , Plant Leaves/chemistry , Rhizophoraceae/microbiology , X-Ray Diffraction/methodsABSTRACT
Four new indole alkaloids, namely, cristatumins A-D (1-4), along with six known congeners (5-10) were identified from the culture extract of Eurotium cristatum EN-220, an endophytic fungus isolated from the marine alga Sargassum thunbergii. The structures of these compounds were established on the basis of extensive spectroscopic analysis. Each of these compounds was evaluated for antimicrobial and insecticidal activity. Compounds 1 and 9 showed antibacterial activity against Escherichia coli and Staphyloccocus aureus, respectively, while compounds 2, 6, and 7 exhibited moderate lethal activity against brine shrimp. Preliminary structure-activity relationships were also discussed.
Subject(s)
Anti-Bacterial Agents/chemistry , Eurotium/chemistry , Indole Alkaloids/chemistry , Anti-Bacterial Agents/pharmacology , Escherichia coli/drug effects , Indole Alkaloids/pharmacology , Models, Molecular , Molecular Structure , Staphylococcus aureus/drug effects , Structure-Activity RelationshipABSTRACT
Penicillium sp. MA-37, which was obtained from the rhizospheric soil of the mangrove plant Bruguiera gymnorrhiza, exhibited different chemical profiles in static and shaken fermentation modes. Three new meroterpenoid derivatives, 4,25-dehydrominiolutelide B (1), 4,25-dehydro-22-deoxyminiolutelide B (2), and isominiolutelide A (3), together with three known ones were characterized from its static fermentation, while three new diphenyl ether derivatives, namely, Δ(1('),3('))-1'-dehydroxypenicillide (4), 7-O-acetylsecopenicillide C (5), and hydroxytenellic acid B (6), along with five related metabolites were isolated from the shaken culture. The structures of these compounds were elucidated on the basis of spectroscopic analysis, and the structure of compound 2 was confirmed by X-ray crystallographic analysis. The absolute configurations of 1-3 and 6 were determined by ECD and modified Mosher's method, respectively. All isolated compounds were evaluated for brine shrimp lethality and antibacterial activity.
Subject(s)
Penicillium/chemistry , Phenyl Ethers/isolation & purification , Rhizophoraceae/microbiology , Terpenes/isolation & purification , Animals , Anti-Bacterial Agents/chemistry , Artemia/drug effects , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Fermentation , Marine Biology , Microbial Sensitivity Tests , Molecular Structure , Phenyl Ethers/chemistry , Phenyl Ethers/pharmacology , Soil Microbiology , Terpenes/chemistry , Terpenes/pharmacologyABSTRACT
Bioassay-guided fractionation of the culture extract of Aspergillus wentii EN-48, an endophytic fungus isolated from an unidentified marine brown algal species of the genus Sargassum, led to the isolation of three new tetranorlabdane diterpenoids, asperolides A-C (1-3), and five related derivatives (4-8). The structures of these compounds were established on the basis of spectroscopic interpretation, and compound 1 was confirmed by X-ray crystallographic analysis. The absolute configuration of 1 was determined by application of the modified Mosher's method. An X-ray structure for wentilactone B (6) is also reported. Compounds 1-8 were evaluated for cytotoxic and antibacterial activities.
Subject(s)
Aspergillus/chemistry , Diterpenes/isolation & purification , Phaeophyceae/chemistry , Ampicillin/pharmacology , Crystallography, X-Ray , Diterpenes/chemistry , Diterpenes/pharmacology , Drug Screening Assays, Antitumor , Female , HeLa Cells , Humans , Marine Biology , Microbial Sensitivity Tests , Molecular Conformation , Molecular Structure , Nuclear Magnetic Resonance, BiomolecularABSTRACT
The marine sediment-derived fungus Penicillium commune QSD-17 was re-investigated and cultured on rice solid medium. Two new compounds, isophomenone (1) and 3-deacetylcitreohybridonol (2), together with seven known derivatives (3-9), were identified. Their structures were determined by spectroscopic analysis.
Subject(s)
Fermentation , Geologic Sediments/microbiology , Penicillium/metabolism , Marine Biology , Metabolism , Molecular Structure , Naphthols , OryzaABSTRACT
In addition to 13 known compounds, four new bisabolane sesquiterpenes, okamurenes A-D (1-4), a new chamigrane derivative, okamurene E (5), and a new C12-acetogenin, okamuragenin (6), were isolated from the marine red alga Laurencia okamurai. The structures of these compounds were determined through detailed spectroscopic analyses. Of these, okamurenes A and B (1 and 2) are the first examples of bromobisabolane sesquiterpenes possessing a phenyl moiety among Laurencia-derived sesquiterpenes, while okamuragenin (6) was the first acetogenin aldehyde possessing a C12-carbon skeleton. Each of the isolated compounds was evaluated for the brine shrimp (Artemia salina) lethal assay and 7-hydroxylaurene displayed potent lethality with LD50 1.8 µM.