Chemical Constituents from the deep-sea-derived Fungus Aureobasidium melanogenum LUO5.

Three new C10 and C12 aliphatic δ-lactones (1-3), three new fatty acid methyl esters (4-6), and eight known compounds (7-14) were isolated from the marine Aureobasidium sp. LUO5. Their structures were established by detailed analyses of the NMR, HRESIMS, optical rotation, and ECD data. All isolates were tested for their inhibitory effects on nitric oxide production in LPS-induced BV-2 cells. Notably, compound 4 displayed the strongest inhibitory effect with the IC50 value of 120.3 nM.

Anti-necroptosis and anti-ferroptosis compounds from the Deep-Sea-Derived fungus Aspergillus sp. MCCC 3A00392.

Eight undescribed (1-8) and 46 known compounds (9-54) were isolated from the deep-sea-derived Aspergillus sp. MCCC 3A00392. Compounds 1-3 were three novel oxoindolo diterpenoids, 4-6 were three bisabolane sesquiterpenoids, while 7 and 8 were two monocyclic cyclopropanes. Their structures were established by exhaustive analyses of the HRESIMS, NMR, and theoretical calculations of the NMR data and ECD spectra. Compounds 10, 33, 38, and 39 were able to inhibit tumor necrosis factor (TNF)-induced necroptosis in murine L929 cell lines. Functional experiments verified that compounds 10 and 39 inhibited necroptosis by downregulating the phosphorylation of RIPK3 and MLKL. Moreover, compound 39 also reduced the phosphorylation of RIPK1. Compounds 10, 33, and 34 displayed potent inhibitory activities against RSL-3 induced ferroptosis with the EC50 value of 3.0 µM, 0.4 µM, and 0.1 µM, respectively. Compound 10 inhibited ferroptosis by the downregulation of HMOX1, while compounds 33 and 34 inhibited ferroptosis through regulation of NRF2/SLC7A11/GCLM axis. However, these compounds only showed weak effect in either the necroptosis or ferroptosis relative mouse disease models. Further studies of pharmacokinetics and pharmacodynamics might improve their in vivo bioactivities.

Hepialiamides A-C: Aminated Fusaric Acid Derivatives and Related Metabolites with Anti-Inflammatory Activity from the Deep-Sea-Derived Fungus Samsoniella hepiali W7.

A systematic investigation combined with a Global Natural Products Social (GNPS) molecular networking approach, was conducted on the metabolites of the deep-sea-derived fungus Samsoniella hepiali W7, leading to the isolation of three new fusaric acid derivatives, hepialiamides A-C (1-3) and one novel hybrid polyketide hepialide (4), together with 18 known miscellaneous compounds (5-22). The structures of the new compounds were elucidated through detailed spectroscopic analysis. as well as TD-DFT-based ECD calculation. All isolates were tested for anti-inflammatory activity in vitro. Under a concentration of 1 µM, compounds 8, 11, 13, 21, and 22 showed potent inhibitory activity against nitric oxide production in lipopolysaccharide (LPS)-activated BV-2 microglia cells, with inhibition rates of 34.2%, 30.7%, 32.9%, 38.6%, and 58.2%, respectively. Of particularly note is compound 22, which exhibited the most remarkable inhibitory activity, with an IC50 value of 426.2 nM.

Chemical Constituents of the Deep-sea Gammarid Shrimp-Derived Fungus Penicillium citrinum XIA-16.

One new alkaloid, (S)-2-acetamido-4-(2-(methylamino)phenyl)-4-oxobutanoic acid (1), was isolated from the deep-sea-derived Penicillium citrinum XIA-16, together with 25 known compounds including ten polyketones (2-11), eight alkaloids (12-19), six steroids (20-25), and a fatty acid (26). Their planar and relative structures were determined by an analysis of 1D and 2D nuclear magnetic resonance (NMR) as well as high resolution electrospray ionization mass spectroscopy (HR-ESI-MS) data. The absolute configuration of 1 was determined by comparison of the experimental and calculated electronic circular dichroism (ECD) spectra. Penicitrinol B (6) significantly inhibited RSL3-induced ferroptosis (EC50 =2.0 µM) by reducing lipid peroxidation and heme oxygenase 1 (HMOX1) expression. Under the concentration of 10 µM, penicitrinol A (7) was able to inhibit cuproptosis with the cell viabilities of 68.2 % compared to the negative control (copper and elesclomol) with the cell viabilities of 14.8 %.

Citriquinolinones A and B: Rare Isoquinolinone-Embedded Citrinin Analogues and Related Metabolites from the Deep-Sea-Derived Aspergillus versicolor 170217.

A systematic chemical investigation of the deep-sea-derived fungus Aspergillus versicolor 170217 resulted in the isolation of six new (1-6) and 45 known (7-51) compounds. The structures of the new compounds were established on the basis of exhaustive analysis of their spectroscopic data and theoretical-statistical approaches including GIAO-NMR, TDDFT-ECD/ORD calculations, DP4+ probability analysis, and biogenetic consideration. Citriquinolinones A (1) and B (2) feature a unique isoquinolinone-embedded citrinin scaffold, representing the first exemplars of a citrinin-isoquinolinone hybrid. Dicitrinones K-L (3-4) are two new dimeric citrinin analogues with a rare CH-CH3 bridge. Biologically, frangula-emodin (32) and diorcinol (17) displayed remarkable anti-food allergic activity with IC50 values of 7.9 ± 3.0 µM and 13.4 ± 1.2 µM, respectively, while diorcinol (17) and penicitrinol A (20) exhibited weak inhibitory activity against Vibrio parahemolyticus, with MIC values ranging from 128 to 256 µM.

Penidihydrocitrinins A-C: New Polyketides from the Deep-Sea-Derived Penicillium citrinum W17 and Their Anti-Inflammatory and Anti-Osteoporotic Bioactivities.

Three new polyketides (penidihydrocitrinins A-C, 1-3) and fourteen known compounds (4-17) were isolated from the deep-sea-derived Penicillium citrinum W17. Their structures were elucidated by comprehensive analyses of 1D and 2D NMR, HRESIMS, and ECD calculations. Compounds 1-17 were evaluated for their anti-inflammatory and anti-osteoporotic bioactivities. All isolates exhibited significant inhibitory effects on LPS-stimulated nitric oxide production in murine brain microglial BV-2 cells in a dose-response manner. Notably, compound 14 displayed the strongest effect with the IC50 value of 4.7 µM. Additionally, compounds 6, 7, and 8 significantly enhanced osteoblast mineralization, which was comparable to that of the positive control, purmorphamine. Furthermore, these three compounds also suppressed osteoclastogenesis in a dose-dependent manner under the concentrations of 2.5 µM, 5.0 µM, and 10 µM.

Neotricitrinols A-C, unprecedented citrinin trimers with anti-osteoporosis activity from the deep-sea-derived Penicillium citrinum W23.

Marine fungi are prolific source for the discovery of structurally diverse and bioactive molecules. In our search for new anti-osteoporosis compounds from deep-sea-derived fungi, we prioritized a fungus whose extract exhibited moderate activity and rich chemical diversity. The investigation of this strain afforded a class of citrinins, including three new citrinin trimers, neotricitrinols A-C (1-3), and three known dimeric/monomeric precursors (4-6). Neotricitrinols A-C (1-3) feature a unique octacyclic carbon scaffold among the few reported citrinin trimers with their absolute configurations established by spectroscopic analysis, theoretical-statistical approaches (GIAO-NMR, TDDFT-ECD/ORD calculations), DP4+ probability analysis as well as biogenetic consideration. A plausible biosynthetic pathway linking 1-3 from the common intermediate metabolite penicitrinol A (4) was proposed. Biologically, neotricitrinol B (2) showed potential anti-osteoporosis activity by promoting osteoblastogenesis and inhibiting adipogenic differentiation on primary bone mesenchymal stem cells, while displaying no cytotoxicity.

Hyposterolactone A, a 3α-Hydroxy Steroidal Lactone from the Deep-Sea-Derived Fungus Hypocrea sp. ZEN14.

Chemical investigation of the deep-sea-derived fungus Hypocrea sp. ZEN14 afforded a new 3α-hydroxy steroidal lactone, hyposterolactone A (1) and 25 known secondary metabolites (2-26). The structure of the new compound was established by detailed spectroscopic analysis, electronic circular dichroism (ECD) calculation as well as a J-based configuration analysis. Compound 10 showed potent cytotoxicity against Huh7 and Jurkat cells with IC50 values of 1.4 µM and 6.7 µM, respectively.

Ferroptosis Inhibitory Compounds from the Deep-Sea-Derived Fungus Penicillium sp. MCCC 3A00126.

Two new xanthones (1 and 2) were isolated from the deep-sea-derived fungus Penicillium sp. MCCC 3A00126 along with 34 known compounds (3-36). The structures of the new compounds were established by spectroscopic data. The absolute configuration of 1 was validated by comparison of experimental and calculated ECD spectra. All isolated compounds were evaluated for cytotoxicity and ferroptosis inhibitory activities. Compounds 14 and 15 exerted potent cytotoxicity against CCRF-CEM cells, with IC50 values of 5.5 and 3.5 µM, respectively, whereas 26, 28, 33, and 34 significantly inhibited RSL3-induced ferroptosis, with EC50 values of 11.6, 7.2, 11.8, and 2.2 µM, respectively.

Tetracyclic Steroids Bearing a Bicyclo[4.4.1] Ring System as Potent Antiosteoporosis Agents from the Deep-Sea-Derived Fungus Rhizopus sp. W23.

Chemical investigation of the deep-sea-derived fungus Rhizopus sp. W23 resulted in the identification of six new (1-3, 6, 8, 9) and 12 known (4, 5, 10-19) cyclocitrinol analogues, together with one handling artifact (7), all featuring an unusual 7/7/6/5-tetracyclic scaffold and bicyclo[4.4.1] A/B rings. Norcyclocitrinoic acids A and B (1, 2) represent the second occurrence of 24,25-bisnor cyclocitrinols. Structures were assigned to new steroids on the basis of extensive spectroscopic analysis and X-ray crystallography. Compound 13 significantly enhances osteoblastogenesis and inhibits adipogenesis in mature bone marrow stromal cells at 5 µM, indicating a potential to be an antiosteoporosis lead.

Chemical Constituents of the Deep-Sea-Derived Penicillium citreonigrum MCCC 3A00169 and Their Antiproliferative Effects.

Six new citreoviridins (citreoviridins J-O, 1-6) and twenty-two known compounds (7-28) were isolated from the deep-sea-derived Penicillium citreonigrum MCCC 3A00169. The structures of the new compounds were determined by spectroscopic methods, including the HRESIMS, NMR, ECD calculations, and dimolybdenum tetraacetate-induced CD (ICD) experiments. Citreoviridins J-O (1-6) are diastereomers of 6,7-epoxycitreoviridin with different chiral centers at C-2-C-7. Pyrenocine A (7), terrein (14), and citreoviridin (20) significantly induced apoptosis for HeLa cells with IC50 values of 5.4 µM, 11.3 µM, and 0.7 µM, respectively. To be specific, pyrenocine A could induce S phase arrest, while terrein and citreoviridin could obviously induce G0-G1 phase arrest. Citreoviridin could inhibit mTOR activity in HeLa cells.

Chemical Constituents of the Deep-Sea-Derived Fungus Cladosporium oxysporum 170103 and Their Antibacterial Effects.

The Cladosporium fungi, one of the largest genera of dematiaceous hyphomycetes, could produce various bioactive secondary metabolites. From the AcOEt-soluble extract of Cladosporium oxysporum 170103, three new secopatulolides (1-3) and thirteen known compounds (4-16) were obtained. Their structures were established by detailed analysis of the NMR and HR-ESI-MS data. All sixteen compounds were tested for antibacterial activity against Vibrio parahemolyticus, ergosterol (10) presented moderate effect with the minimum inhibitory concentration (MIC) of 32 µM. It can destruct the membrane integrity of Vibrio parahemolyticus to change the cell shape.

Brefeldin A from the Deep-Sea-Derived Fungus Fusarium sp. Targets on RIPK3 to Inhibit TNFα-Induced Necroptosis.

From the deep-sea-derived Fusarium sp. ZEN-48, four known compounds were obtained. Their structures were established by extensive analyses of the NMR, HR-ESI-MS, and the X-ray crystallographic data as brefeldin A (BFA, 1), brevianamide F (2), N-acetyltryptamine (3), and (+)-diaporthin (4). Although BFA was extensively investigated for its potent bioactivities, its role on TNFα-induced necroptosis was incompletely understood. In this study, BFA showed significant inhibition on TNFα-induced necroptosis by disrupting the necrosome formation and suppressing the phosphorylation of RIPK3 and MLKL (IC50 =0.5 µM). While, it had no effect on TNFα-induced NF-κB/MAPKs activation and apoptosis. The finding raised significant implications of BFA for necroptosis-related inflammatory disease therapy and new drug development from marine fungi.