Apoptotic Activity of New Oxisterigmatocystin Derivatives from the Marine-Derived Fungus Aspergillus nomius NC06

Sponge-derived fungi have recently attracted attention as an important source of interesting bioactive compounds. Aspergillus nomius NC06 was isolated from the marine sponge Neopetrosia chaliniformis. This fungus was cultured on rice medium and yielded four compounds including three new oxisterigmatocystins, namely, J, K, and L (1, 2, and 3), and one known compound, aspergillicin A (4). Structures of the compounds were elucidated by 1D and 2D NMR spectroscopy and by high-resolution mass spectrometry. The isolated compounds were tested for cytotoxic activity against HT 29 colon cancer cells, where compounds 1, 2, and 4 exhibited IC₅₀ values of 6.28, 15.14, and 1.63 µM, respectively. Under the fluorescence microscope by using a double staining method, HT 29 cells were observed to be viable, apoptotic, and necrotic after treatment with the cytotoxic compounds 1, 2, and 4. The result shows that compounds 1 and 2 were able to induce apoptosis and cell death in HT 29 cells.     

New Prenylated Indole Homodimeric and Pteridine Alkaloids from the Marine-Derived Fungus Aspergillus austroafricanus Y32-2

Chemical investigation of secondary metabolites from the marine-derived fungus Aspergillus austroafricanus Y32-2 resulted in the isolation of two new prenylated indole alkaloid homodimers, di-6-hydroxydeoxybrevianamide E (1) and dinotoamide J (2), one new pteridine alkaloid asperpteridinate A (3), with eleven known compounds (4–14). Their structures were elucidated by various spectroscopic methods including HRESIMS and NMR, while their absolute configurations were determined by ECD calculations. Each compound was evaluated for pro-angiogenic, anti-inflammatory effects in zebrafish models and cytotoxicity for HepG2 human liver carcinoma cells. As a result, compounds 2, 4, 5, 7, 10 exhibited pro-angiogenic activity in a PTK787-induced vascular injury zebrafish model in a dose-dependent manner, compounds 7, 8, 10, 11 displayed anti-inflammatory activity in a CuSO₄-induced zebrafish inflammation model, and compound 6 showed significant cytotoxicity against HepG2 cells with an IC₅₀ value of 30 µg/mL.     

Polyketides and Meroterpenes from the Marine-Derived Fungi Aspergillus unguis 158SC-067 and A. flocculosus 01NT-1.1.5 and Their Cytotoxic and Antioxidant Activities

Ten secondary metabolites, including a new grifolin analog, grifolin B (1); a new homovalencic acid derivative, 12-hydroxyhomovalencic acid (7); and a compound isolated from a natural source for the first time (9), along with seven known compounds, grifolin (2), averantin (3), 7-chloroaverantin (4), 1′-O-methylaverantin (5), 7-hydroxy-2-(2-hydroxypropyl)-5-pentylchromone (6), homovalencic acid (8), and bekeleylactone E (10), were isolated from two fungal strains. The structures of 1–10 were identified by detailed analysis and comparison of their spectroscopic data with literature values. Compounds 9 and 10 showed moderate cytotoxic activity against a panel of cancer cell lines (PC-3, HCT-15, MDA-MB-231, ACHN, NCI-H23, NUGC-3), with the GI₅₀ values ranging from 1.1 µM to 3.6 µM, whereas 1 displayed a weak 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity without cytotoxicity against all tested cell lines.     

Six New Antimicrobial Metabolites from the Deep-Sea Sediment-Derived Fungus Aspergillus fumigatus SD-406

Six new metabolites, including a pair of inseparable mixtures of secofumitremorgins A (1a) and B (1b), which differed in the configuration of the nitrogen atom, 29-hydroxyfumiquinazoline C (6), 10R-15-methylpseurotin A (7), 1,4,23-trihydroxy-hopane-22,30-diol (10), and sphingofungin I (11), together with six known compounds (2–5 and 8–9), were isolated and identified from the deep-sea sediment-derived fungus Aspergillus fumigatus SD-406. Their structures were determined by detailed spectroscopic analysis of NMR and MS data, chiral HPLC analysis of the acidic hydrolysate, X-ray crystallographic analysis, J-based configuration analysis, and quantum chemical calculations of ECD, OR, and NMR (with DP4+ probability analysis). Among the compounds, 1a/1b represent a pair of novel scaffolds derived from indole diketopiperazine by cleavage of the amide bond following aromatization to give a pyridine ring. Compounds 1, 4, 6, 7, 10 and 11 showed inhibitory activities against pathogenic bacteria and plant pathogenic fungus, with MIC values ranging from 4 to 64 μg/mL.     

Anti-Inflammatory Activity of Tanzawaic Acid Derivatives from a Marine-Derived Fungus Penicillium steckii 108YD142

Chemical investigation of a marine-derived fungus, Penicillium steckii 108YD142, resulted in the discovery of a new tanzawaic acid derivative, tanzawaic acid Q (1), together with four known analogues, tanzawaic acids A (2), C (3), D (4), and K (5). The structures of tanzawaic acid derivatives 1–5 were determined by the detailed analysis of 1D, 2D NMR and LC-MS data, along with chemical methods and literature data analysis. These compounds significantly inhibited nitric oxide (NO) production and the new tanzawaic acid Q (1) inhibited the lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins and mRNA expressions in RAW 264.7 macrophages. Additionally, compound 1 reduced the mRNA levels of inflammatory cytokines. Taken together, the results of this study demonstrated that the new tanzawaic acid derivative inhibits LPS-induced inflammation. This is the first report on the anti-inflammatory activity of tanzawaic acid Q (1).     

New Monoterpenoids and Polyketides from the Deep-Sea Sediment-Derived Fungus Aspergillus sydowii MCCC 3A00324

Chemical study of the secondary metabolites of a deep-sea-derived fungus Aspergillus sydowii MCCC 3A00324 led to the isolation of eleven compounds (1–11), including one novel (1) and one new (2) osmane-related monoterpenoids and two undescribed polyketides (3 and 4). The structures of the metabolites were determined by comprehensive analyses of the NMR and HRESIMS spectra, in association with quantum chemical calculations of the ¹³C NMR, ECD, and specific rotation data for the configurational assignment. Compound 1 possessed a novel monoterpenoid skeleton, biogenetically probably derived from the osmane-type monoperpenoid after the cyclopentane ring cleavage and oxidation reactions. Additionally, compound 3 was the first example of the α-pyrone derivatives bearing two phenyl units at C-3 and C-5, respectively. The anti-inflammatory activities of 1–11 were tested. As a result, compound 6 showed potent inhibitory nitric oxide production in lipopolysaccharide (LPS)-activated BV-2 microglia cells with an inhibition rate of 94.4% at the concentration of 10 µM. In addition, a plausible biosynthetic pathway for 1 and 2 was also proposed.     

Nitrogen-Containing Secondary Metabolites from a Deep-Sea Fungus Aspergillus unguis and Their Anti-Inflammatory Activity

Aspergillus is well-known as the second-largest contributor of fungal natural products. Based on NMR guided isolation, three nitrogen-containing secondary metabolites, including two new compounds, variotin B (1) and coniosulfide E (2), together with a known compound, unguisin A (3), were isolated from the ethyl acetate (EtOAc) extract of the deep-sea fungus Aspergillus unguis IV17-109. The planar structures of 1 and 2 were elucidated by an extensive analysis of their spectroscopic data (HRESIMS, 1D and 2D NMR). The absolute configuration of 2 was determined by comparison of its optical rotation value with those of the synthesized analogs. Compound 2 is a rare, naturally occurring substance with an unusual cysteinol moiety. Furthermore, 1 showed moderate anti-inflammatory activity with an IC₅₀ value of 20.0 µM. These results revealed that Aspergillus unguis could produce structurally diverse nitrogenous secondary metabolites, which can be used for further studies to find anti-inflammatory leads.     

New Andrastin-Type Meroterpenoids from the Marine-Derived Fungus Penicillium sp.

Three new andrastin-type meroterpenoids penimeroterpenoids A–C (1–3) together with two known analogs (4 and 5) were isolated from the cultures of the marine-derived Penicillium species (sp.). The structures of the new compounds were elucidated on the basis of 1- and 2-dimensional (1D/2D) Nuclear Magnetic Resonance (NMR) spectroscopic and mass spectrometric analysis. The absolute configurations of 1–3 were determined by comparison of experimental and calculated electronic circular dichroism (ECD) spectra. Compound 1 showed moderate cytotoxicity against A549, HCT116, and SW480 cell lines.     

New Secondary Metabolites from the Marine-Derived Fungus Talaromyces mangshanicus BTBU20211089

Seven new compounds, namely talaromanloid A (1), talaromydene (2), 10-hydroxy-8-demethyltalaromydine and 11-hydroxy-8-demethyltalaromydine (3 and 4), talaromylectone (5), and ditalaromylectones A and B (6 and 7), together with seven known compounds were identified from a marine-derived fungus, Talaromyces mangshanicus BTBU20211089, which was isolated from a sediment sample collected from the South China Sea. Their chemical structures were determined using spectroscopic data, including HRESIMS, 1D, and 2D NMR techniques. The absolute configurations of 1 and 2 were elucidated by comparing experimental and calculated ECD spectra. Compounds 1, 2, 6, and 7 are new compounds possessing a novel carbon skeleton. Compound 6 is a dimeric molecule of 3 and 9. Compound 7 shared a unique structure of the cyclized dimer of 3 and 4. All the compounds were tested for their bioactivities against Staphylococcus aureus, Escherichia coli, and Candida albicans.     

New Meroterpenoids from the Endophytic Fungus Aspergillus flavipes AIL8 Derived from the Mangrove Plant Acanthus ilicifolius

Four new meroterpenoids (2–5), along with three known analogues (1, 6, and 7) were isolated from mangrove plant Acanthus ilicifolius derived endophytic fungus Aspergillus flavipes. The structures of these compounds were elucidated by NMR and MS analysis, the configurations were assigned by CD data, and the stereochemistry of 1 was confirmed by X-ray crystallography analysis. A possible biogenetic pathway of compounds 1–7 was also proposed. All compounds were evaluated for antibacterial and cytotoxic activities.     

New Isocoumarin Analogues from the Marine-Derived Fungus Paraphoma sp. CUGBMF180003

Nine new secondary metabolites, including six isocoumarin analogues, 7-hydroxyoospolactone (1), 7-methoxyoospolactone (2), 7-methoxy-9-hydroxyoospolactone (3), 10-acetoxy-9-hydroxyoospolactone (4), 6-dehydroxysescandelin (5), parapholactone (6), and three compounds with a rare skeleton of isocoumarin coupled with phenylethylamine, namely paraphamide A (12), paraphamide B (13), and paraphamide C (14), together with five known compounds, oospolactone (7), 8-O-methyloospolactone (8), 10-hydroxyoospolactone (9), 9,10-dihydroxyoospolactone (10), and oospoglycol (11), were isolated and identified from the marine-derived fungus Paraphoma sp. CUGBMF180003. Their chemical structures were determined using spectroscopic data, including HRESIMS and 1D and 2D NMR techniques. Furthermore, the stereogenic carbons in 5 and 14 were determined by comparing the experimental and calculated electronic circular dichroism (ECD) spectra. The carbon skeleton of 12–14 was identified as the first example of isocoumarin coupled with phenylethylamine derivatives. All of these compounds were examined for antimicrobial activities against Candida albicans and Staphylococcus aureus. Both 1 and 6 showed antibacterial activity against S. aureus with MIC values of 12.5 μg/mL.     

New Ophiobolins from the Deep-Sea Derived Fungus Aspergillus sp. WHU0154 and Their Anti-Inflammatory Effects

Deep-sea fungi have become a new arsenal for the discovery of leading compounds. Here five new ophiobolins 1–5, together with six known analogues 6–11, obtained from a deep-sea derived fungus WHU0154. Their structures were determined by analyses of IR, HR-ESI-MS, and NMR spectra, along with experimental and calculated electronic circular dichroism (ECD) analysis. Pharmacological studies showed that compounds 4 and 6 exhibited obvious inhibitory effects on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in murine macrophage RAW264.7 cells. Mechanical study revealed that compound 6 could inhibit the inducible nitric oxide synthase (iNOS) level in LPS-stimulated RAW264.7 cells. In addition, compounds 6, 9, and 10 could significantly inhibit the expression of cyclooxygenase 2 (COX 2) in LPS-induced RAW264.7 cells. Preliminary structure-activity relationship (SAR) analyses revealed that the aldehyde group at C-21 and the α, β-unsaturated ketone functionality at A ring in ophiobolins were vital for their anti-inflammatory effects. Together, the results demonstrated that ophiobolins, especially for compound 6, exhibited strong anti-inflammatory effects and shed light on the discovery of ophiobolins as new anti-inflammatory agents.     

Bioactive Indole Diketopiperazine Alkaloids from the Marine Endophytic Fungus Aspergillus sp. YJ191021

Six new prenylated indole diketopiperazine alkaloids, asperthrins A–F (1–6), along with eight known analogues (7–14), were isolated from the marine-derived endophytic fungus Aspergillus sp. YJ191021. Their planar structures and absolute configurations were elucidated by HR-ESI-MS, 1D/2D NMR data, and time-dependent density functional theory (TDDFT)/ECD calculation. The isolated compounds were assayed for their inhibition against three agricultural pathogenic fungi, four fish pathogenic bacteria, and two agricultural pathogenic bacteria. Compound 1 exhibited moderate antifungal and antibacterial activities against Vibrio anguillarum, Xanthomonas oryzae pv. Oryzicola, and Rhizoctonia solani with minimal inhibitory concentration (MIC) values of 8, 12.5, and 25 μg/mL, respectively. Furthermore, 1 displayed notable anti-inflammatory activity with IC₅₀ value of 1.46 ± 0.21 μM in Propionibacterium acnes induced human monocyte cell line (THP-1).     

New Alkylpyridinium Anthraquinone,Isocoumarin, C-Glucosyl Resorcinol Derivative and Prenylated Pyranoxanthones from the Culture of a Marine Sponge-Associated Fungus,Aspergillus stellatus KUFA 2017

An unreported isocoumarin, (3S,4R)-4-hydroxy-6-methoxymellein (2), an undescribed propylpyridinium anthraquinone (4), and an unreported C-glucosyl resorcinol derivative, acetyl carnemycin E (5c), were isolated, together with eight previously reported metabolites including p-hydroxybenzaldehyde (1), 1,3-dimethoxy-8-hydroxy-6-methylanthraquinone (3a), 1,3-dimethoxy-2,8-dihydroxy-6-methylanthraquinone (3b), emodin (3c), 5[(3E,5E)-nona-3,5-dien-1-yl]benzene (5a), carnemycin E (5b), tajixanthone hydrate (6a) and 15-acetyl tajixanthone hydrate (6b), from the ethyl acetate extract of the culture of a marine sponge-derived fungus, Aspergillus stellatus KUFA 2017. The structures of the undescribed compounds were elucidated by 1D and 2D NMR and high resolution mass spectral analyses. In the case of 2, the absolute configurations of the stereogenic carbons were determined by comparison of their calculated and experimental electronic circular dichroism (ECD) spectra. The absolute configurations of the stereogenic carbons in 6a and 6b were also determined, for the first time, by X-ray crystallographic analysis. Compounds 2, 3a, 3b, 4, 5a, 5b, 5c, 6a, and 6b were assayed for antibacterial activity against four reference strains, viz. two Gram-positive (Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212) and two Gram-negative (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853), as well as three multidrug-resistant strains. However, only 5a exhibited significant antibacterial activity against both reference and multidrug-resistant strains. Compound 5a also showed antibiofilm activity against both reference strains of Gram-positive bacteria.     

Eremophilane-Type Sesquiterpenes from a Marine-Derived Fungus Penicillium Copticola with Antitumor and Neuroprotective Activities

Chemical examination of a marine sponge-associated Penicillium copticola fungus resulted in the isolation of ten undescribed eremophilanes, namely copteremophilanes A–J (1–10), along with two new glycosides, 5-glycopenostatin F (11) and 5-glucopenostatin I (12). Their structures were determined by extensive spectroscopic data, in association with ECD data and chemical conversions for configurational assignments. Analogs 1, 2, and 10 represent a group of uncommon skeletons of eremophilanes with an aromatic ring and a methyl migration from C-5 to C-9, and analogs 11 and 12 are characteristic of a PKS scaffold bearing a glucose unit. The incorporation of a chlorinated phenylacetic unit in 3–9 is rarely found in nature. Analog 7 showed neuroprotective effect, whereas 8 exhibited selective inhibition against human non-small cell lung cancer cells (A549). This study enriched the chemical diversity of eremophilanes and extended their bioactivities to neuroprotection.     

Mitochondrial Targeting in an Anti-Austerity Approach Involving Bioactive Metabolites Isolated from the Marine-Derived Fungus Aspergillus sp.

The tumor microenvironment is a nutrient-deficient region that alters the cancer cell phenotype to aggravate cancer pathology. The ability of cancer cells to tolerate nutrient starvation is referred to as austerity. Compounds that preferentially target cancer cells growing under nutrient-deficient conditions are being employed in anti-austerity approaches in anticancer drug discovery. Therefore, in this study, we investigated physcion (1) and 2-(2′,3-epoxy-1′,3′,5′-heptatrienyl)-6-hydroxy-5-(3-methyl-2-butenyl) benzaldehyde (2) obtained from a culture extract of the marine-derived fungus Aspergillus species (sp.), which were isolated from an unidentified marine sponge, as anti-austerity agents. The chemical structures of 1 and 2 were determined via spectroscopic analysis and comparison with authentic spectral data. Compounds 1 and 2 exhibited selective cytotoxicity against human pancreatic carcinoma PANC-1 cells cultured under glucose-deficient conditions, with IC₅₀ values of 6.0 and 1.7 µM, respectively. Compound 2 showed higher selective growth-inhibitory activity (505-fold higher) under glucose-deficient conditions than under general culture conditions. Further analysis of the mechanism underlying the anti-austerity activity of compounds 1 and 2 against glucose-starved PANC-1 cells suggested that they inhibited the mitochondrial electron transport chain.     

Noonindoles A–F: Rare Indole Diterpene Amino Acid Conjugates from a Marine-Derived Fungus,Aspergillus noonimiae CMB-M0339

Analytical scale chemical/cultivation profiling prioritized the Australian marine-derived fungus Aspergillus noonimiae CMB-M0339. Subsequent investigation permitted isolation of noonindoles A–F (5–10) and detection of eight minor analogues (i–viii) as new examples of a rare class of indole diterpene (IDT) amino acid conjugate, indicative of an acyl amino acid transferase capable of incorporating a diverse range of amino acid residues. Structures for 5–10 were assigned by detailed spectroscopic and X-ray crystallographic analysis. The metabolites 5–14 exhibited no antibacterial properties against G-ve and G+ve bacteria or the fungus Candida albicans, with the exception of 5 which exhibited moderate antifungal activity.     

Antiproliferative Illudalane Sesquiterpenes from the Marine Sediment Ascomycete Aspergillus oryzae

The new asperorlactone (1), along with the known illudalane sesquiterpene echinolactone D (2), two known pyrones, 4-(hydroxymethyl)-5-hydroxy-2H-pyran-2-one (3) and its acetate 4, and 4-hydroxybenzaldehyde (5), were isolated from a culture of Aspergillus oryzae, collected from Red Sea marine sediments. The structure of asperorlactone (1) was elucidated by HR-ESIMS, 1D, and 2D NMR, and a comparison between experimental and DFT calculated electronic circular dichroism (ECD) spectra. This is the first report of illudalane sesquiterpenoids from Aspergillus fungi and, more in general, from ascomycetes. Asperorlactone (1) exhibited antiproliferative activity against human lung, liver, and breast carcinoma cell lines, with IC₅₀ values < 100 µM. All the isolated compounds were also evaluated for their toxicity using the zebrafish embryo model.     

Bioactive Phenylalanine Derivatives and Cytochalasins from the Soft Coral-Derived Fungus,Aspergillus elegans

One new phenylalanine derivative 4′-OMe-asperphenamate (1), along with one known phenylalanine derivative (2) and two new cytochalasins, aspochalasin A1 (3) and cytochalasin Z24 (4), as well as eight known cytochalasin analogues (5–12) were isolated from the fermentation broth of Aspergillus elegans ZJ-2008010, a fungus obtained from a soft coral Sarcophyton sp. collected from the South China Sea. Their structures and the relative configurations were elucidated using comprehensive spectroscopic methods. The absolute configuration of 1 was determined by chemical synthesis and Marfey’s method. All isolated metabolites (1–12) were evaluated for their antifouling and antibacterial activities. Cytochalasins 5, 6, 8 and 9 showed strong antifouling activity against the larval settlement of the barnacle Balanus amphitrite, with the EC₅₀ values ranging from 6.2 to 37 μM. This is the first report of antifouling activity for this class of metabolites. Additionally, 8 exhibited a broad spectrum of antibacterial activity, especially against four pathogenic bacteria Staphylococcus albus, S. aureus, Escherichia coli and Bacillus cereus.     

Cyclodepsipeptides and Other O-Containing Heterocyclic Metabolites from Beauveria felina EN-135, a Marine-Derived Entomopathogenic Fungus

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.