New piperazine derivatives helvamides B-C from the marine-derived fungus Penicillium velutinum ZK-14 uncovered by OSMAC (One Strain Many Compounds) strategy.

Four extracts of the marine-derived fungus Penicillium velutinum J.F.H. Beyma were obtained via metal ions stress conditions based on the OSMAC (One Strain Many Compounds) strategy. Using a combination of modern approaches such as LC/UV, LC/MS and bioactivity data analysis, as well as in silico calculations, influence metal stress factors to change metabolite profiles Penicillium velutinum were analyzed. From the ethyl acetate extract of the P. velutinum were isolated two new piperazine derivatives helvamides B (1) and C (2) together with known saroclazin A (3) (4S,5R,7S)-4,11-dihydroxy-guaia-1(2),9(10)-dien (4). Their structures were established based on spectroscopic methods. The absolute configuration of helvamide B (1) as 2R,5R was determined by a combination of the X-ray analysis and by time-dependent density functional theory (TD-DFT) calculations of electronic circular dichroism (ECD) spectra. The cytotoxic activity of the isolated compounds against human prostate cancer PC-3 and human embryonic kidney HEK-293 cells and growth inhibition activity against yeast-like fungi Candida albicans were assayed.

Bioactive Polyketides from the Natural Complex of the Sea Urchin-Associated Fungi Penicillium sajarovii KMM 4718 and Aspergillus protuberus KMM 4747.

The marine-derived fungal strains KMM 4718 and KMM 4747 isolated from sea urchin Scaphechinus mirabilis as a natural fungal complex were identified as Penicillium sajarovii and Aspergillus protuberus based on Internal Transcribed Spacer (ITS), partial ß-tubulin (BenA), and calmodulin (CaM) molecular markers as well as an ribosomal polymerase two, subunit two (RPB2) region for KMM 4747. From the ethyl acetate extract of the co-culture, two new polyketides, sajaroketides A (1) and B (2), together with (2'S)-7-hydroxy-2-(2'-hydroxypropyl)-5-methylchromone (3), altechromone A (4), norlichexanthone (5), griseoxanthone C (6), 1,3,5,6-tetrahydroxy-8-methylxanthone (7), griseofulvin (8), 6-O-desmethylgriseofulvin (9), dechlorogriseofulvin (10), and 5,6-dihydro-4-methyl-2H-pyran-2-one (11) were identified. The structures of the compounds were elucidated using spectroscopic analyses. The absolute configurations of the chiral centers of sajaroketides A and B were determined using time-dependent density functional theory (TDDFT)-based calculations of the Electronic Circular Dichroism (ECD) spectra. The inhibitory effects of these compounds on urease activity and the growth of Staphylococcus aureus, Escherichia coli, and Candida albicans were observed. Sajaroketide A, altechromone A, and griseofulvin showed significant cardioprotective effects in an in vitro model of S. aureus-induced infectious myocarditis.

The Metabolite Profiling of Aspergillus fumigatus KMM4631 and Its Co-Cultures with Other Marine Fungi.

An Aspergillus fumigatus KMM 4631 strain was previously isolated from a Pacific soft coral Sinularia sp. sample and was found to be a source of a number of bioactive secondary metabolites. The aims of this work are the confirmation of this strain' identification based on ITS, BenA, CaM, and RPB2 regions/gene sequences and the investigation of secondary metabolite profiles of Aspergillus fumigatus KMM 4631 culture and its co-cultures with Penicillium hispanicum KMM 4689, Amphichorda sp. KMM 4639, Penicillium sp. KMM 4672, and Asteromyces cruciatus KMM 4696 from the Collection of Marine Microorganisms (PIBOC FEB RAS, Vladivostok, Russia). Moreover, the DPPH-radical scavenging activity, urease inhibition, and cytotoxicity of joint fungal cultures' extracts on HepG2 cells were tested. The detailed UPLC MS qTOF investigation resulted in the identification and annotation of indolediketopiperazine, quinazoline, and tryptoquivaline-related alkaloids as well as a number of polyketides (totally 20 compounds) in the extract of Aspergillus fumigatus KMM 4631. The metabolite profiles of the co-cultures of A. fumigatus with Penicillium hispanicum, Penicillium sp., and Amphichorda sp. were similar to those of Penicillium hispanicum, Penicillium sp., and Amphichorda sp. monocultures. The metabolite profile of the co-culture of A. fumigatus with Asteromyces cruciatus differed from that of each monoculture and may be more promising for the isolation of new compounds.

New Cyclopiane Diterpenes and Polyketide Derivatives from Marine Sediment-Derived Fungus Penicillium antarcticum KMM 4670 and Their Biological Activities.

Two new cyclopiane diterpenes and a new cladosporin precursor, together with four known related compounds, were isolated from the marine sediment-derived fungus Penicillium antarcticum KMM 4670, which was re-identified based on phylogenetic inference from ITS, BenA, CaM, and RPB2 gene regions. The absolute stereostructures of the isolated cyclopianes were determined using modified Mosher's method and quantum chemical calculations of the ECD spectra. The isolation from the natural source of two biosynthetic precursors of cladosporin from a natural source has been reported for the first time. The antimicrobial activities of the isolated compounds against Staphylococcus aureus, Escherichia coli, and Candida albicans as well as the inhibition of staphylococcal sortase A activity were investigated. Moreover, the cytotoxicity of the compounds to mammalian cardiomyocytes H9c2 was studied. As a result, new cyclopiane diterpene 13-epi-conidiogenone F was found to be a sortase A inhibitor and a promising anti-staphylococcal agent.

New Anti-Hypoxic Metabolites from Co-Culture of Marine-Derived Fungi Aspergillus carneus KMM 4638 and Amphichorda sp. KMM 4639.

The KMM 4639 strain was identified as Amphichorda sp. based on two molecular genetic markers: ITS and ß-tubulin regions. Chemical investigation of co-culture marine-derived fungi Amphichorda sp. KMM 4639 and Aspergillus carneus KMM 4638 led to the identification of five new quinazolinone alkaloids felicarnezolines A-E (1-5), a new highly oxygenated chromene derivative oxirapentyn M (6) and five previously reported related compounds. Their structures were established using spectroscopic methods and by comparison with related known compounds. The isolated compounds showed low cytotoxicity against human prostate and breast cancer cells but felicarnezoline B (2) protected rat cardiomyocytes H9c2 and human neuroblastoma SH-SY5Y cells against CoCl2-induced damage.

Meroantarctines A-C, Meroterpenoids with Rearranged Skeletons from the Alga-Derived Fungus Penicillium antarcticum KMM 4685 with Potent p-Glycoprotein Inhibitory Activity.

New meroterpenoids, meroantarctines A-C (1-3), with unique 6/5/6/6, 6/5/6/5/6, and 6/5/6/5 polycyclic systems were isolated from the alga-derived fungus Penicillium antarcticum KMM 4685. Their structures were elucidated by spectroscopic methods, X-ray diffraction, and quantum chemical calculations. A biogenetic pathway for 1-3 was proposed. Meroantarctines A-C (1-3) inhibited p-glycoprotein activity and could resensitize drug-resistant cancer cells to docetaxel.

New dihydrobenzofuranoid from the marine-derived fungus Aspergillus ustus KMM 4664.

One new dihydrobenzofuran derivative (1), known depsipeptide emericellamide A (2), three known drimanes (3-5) and two artifact drimane derivatives (6, 7) were isolated from the marine-derived fungus Aspergillus ustus KMM 4664. Their structures were determined by detailed analysis of spectroscopic data and by comparison with related known compounds. The absolute configuration of 1 was determined by time-dependent density functional theory (TD-DFT) calculations of ECD spectra. Compound 7 showed significant ability of the inhibition of spermatozoa to fertilize egg-cells of the sea urchin Strongylocentrotus intermedius with IC50 value 21 µM.

Naphto-Γ-pyrones from the marine-derived fungus Aspergillus foetidus.

Nine naphto-γ-pyrones rubrofusarine B (1), TMC 256 A1 (2), fansecinones A (3) and B (4), aurasperones A (5), B (6) and F (7), dianhydro-aurasperone C (8) and asperpyrone B (9) were isolated from the marine-derived fungus Aspergillus foetidus KMM 4694. Their structures were established based on spectroscopic methods. The effect of the substances on viability and colony formation of human drug-resistant prostate cancer 22Rv1 cell was evaluated.

Pallidopenillines: Polyketides from the Alga-Derived Fungus Penicillium thomii Maire KMM 4675.

Eleven new polyketides, pallidopenillines 1-11, were isolated from the alga-derived fungus Penicillium thomii. The structures of these compounds were established based on spectroscopic methods. The absolute configuration of pallidopenilline A (1) as 4R, 5S, 8S, 9R, 10R, 13R was established using a combination of the modified Mosher's method, X-ray analysis, and NOESY data. The absolute configurations of 2-5 were determined by time-dependent density functional theory calculations of the ECD spectra and ECD and NOESY data. It was shown that 1-acetylpallidopenilline A (2) and pallidopenilline G (10) inhibit the growth of colonies of 22Rv1 cells by 40% at 2 and 1 µM, respectively.

Pretrichodermamides D-F from a Marine Algicolous Fungus Penicillium sp. KMM 4672.

Three new epidithiodiketopiperazines pretrichodermamides D-F (1-3), together with the known N-methylpretrichodermamide B (4) and pretrichodermamide С (5), were isolated from the lipophilic extract of the marine algae-derived fungus Penicillium sp. KMM 4672. The structures of compounds 1-5 were determined based on spectroscopic methods. The absolute configuration of pretrichodermamide D (1) was established by a combination of modified Mosher's method, NOESY data, and biogenetic considerations. N-Methylpretrichodermamide B (5) showed strong cytotoxicity against 22Rv1 human prostate cancer cells resistant to androgen receptor targeted therapies.

New 6,6-Spiroketal from the Alga-Derived Fungus Penicillium lividum.

The new 6,6-spiroketal,sargassopenilline H (1), and known peneciraistin C (2) have been isolated from an EtOAc extract of the marine-derived fungus Penicillium lividumKMM 4663. The structure of the new metabolite was determined by HR ESIMS and 1D and 2D NMR spectroscopy. Sargassopenilline H (1) in non-cytotoxic concentration inhibited colony formation of RPMI-7951 and MDA-MB-231 cell lines.

New Metabolites from a Marine Sediment-Derived Fungus, Aspergillus carneus.

A new polyketide 1 and a new decaline derivative 2 were isolated from a sediment-derived fungus Aspergillus carneus Blochwitz, together with one known bisabolane sesquiterpenoid and seven known polyketide metabolites. The structures of the isolated compounds were established by HR-MS, and 1D and 2D NMR spectroscopy. The cytotoxic and antiradical activities of the isolated compounds were evaluated.

Sargassopenillines A-G, 6,6-spiroketals from the alga-derived fungi Penicillium thomii and Penicillium lividum.

Seven new 6,6-spiroketals, sargassopenillines A-G (1-7) were isolated from the alga-derived fungi Penicillium thomii KMM 4645 and Penicillium lividum KMM 4663. The structures of these metabolites were determined by HR-MS and 1D and 2D NMR. The absolute configurations of compounds 1, 5 and 6 were assigned by the modified Mosher's method and by CD data. Sargassopenilline C (3) inhibited the transcriptional activity of the oncogenic nuclear factor AP-1 with an IC50 value of 15 µM.

Oxirapentyns F-K from the marine-sediment-derived fungus Isaria felina KMM 4639.

Six new highly oxygenated chromene derivatives, oxirapentyns F-K (2-7), one new polyketide (8), one new benzofurane (9), and two known cyclodepsipeptides, isoisariin B and isaridin E, were isolated from the lipophilic extract of the marine-derived fungus Isaria felina KMM 4639. The structures of compounds 2-9 were determined using spectroscopic methods. The relative configurations of compounds 2-7 were established through a combination of NOE data and spin coupling constants, and these results were confirmed by X-ray crystallographic analysis of 4. The absolute structures of all oxirapentyns were assumed based on their biogenetic relationship and confirmed using the modified Mosher's method on 2 and 7. Isariketide (8) showed moderate cytotoxicity toward HL-60 cells.

Meroterpenoids from the alga-derived fungi Penicillium thomii Maire and Penicillium lividum Westling.

Ten new austalide meroterpenoids (1-10) were isolated from the alga-derived fungi Penicillium thomii KMM 4645 and Penicillium lividum KMM 4663. Their structures were elucidated by extensive spectroscopic analysis and by comparison with related known compounds. The absolute configurations of some of the metabolites were assigned by the modified Mosher's method and CD data. Compounds 1, 2, 8, and 9 were able to inhibit AP-1-dependent transcriptional activity in JB6 Cl41 cell lines at noncytotoxic concentrations. Austalides 1-5, 8, and 9 exhibited significant inhibitory activity against endo-1,3-ß-D-glucanase from a crystalline stalk of the marine mollusk Pseudocardium sachalinensis.

New metabolites from the algal associated marine-derived fungus Aspergillus carneus.

The new oxepin-containing (1) and quinazolinone (2) alkaloids and new dihydrobenzofuran derivative (3) have been isolated from a marine strain of Aspergillus carneus KMM 4638. The structures of these metabolites were determined by HR-MS and 1D and 2D NMR, along with Marfey's method.