Four sulfur-containing compounds with anti-colon cancer effect from marine-derived fungus Aspergillus terreus.

Sulfur-containing natural products possess a variety of biological functions including antitumor, antibacterial, anti-inflammatory and antiviral activities. In this study, four previously undescribed sulfur-containing compounds asperteretals L and M, terreins A and B, together with 17 known compounds were obtained from a culture of marine fungus A. terreus supplemented with inorganic sulfur source Na2SO4. Their planar structures and absolute configurations were elucidated by NMR, HRESIMS, and ECD experiments. The in vitro cytotoxicities of compounds 1-21 against HCT-116 and Caco-2 were evaluated by SRB assay. Asperteretal M (2) exhibited activity against HCT-116 with the IC50 value at 30µM. The antiproliferative effect of asperteretal M was confirmed by colony formation assay and cell death staining. Furthermore, the preliminary study on the anti-colon cancer mechanism of asperteretal M was performed by RNA-seq analysis. Western blotting validated that asperteretal M significantly decreased the expression of cell-cycle regulatory proteins CDK1, CDK4, and PCNA in a concentration-dependent manner.

Isolation and stereospecific synthesis of indole alkaloids with lipid-lowering effects from the marine-derived fungus Colletotrichum gloeosporioides BB4.

Seven undescribed compounds, colletotrichindoles A-E, colletotrichaniline A, and colletotrichdiol A, as well as three known compounds, (-)-isoalternatine A, (+)-alternatine A and 3-hydroxybutan-2-yl 2-phenylacetate were isolated from the marine-derived fungus Colletotrichu gloeosporioides BB4. The racemic mixtures colletotrichindole A，colletotrichindole C, and colletotrichdiol A were further separated by chiral chromatography to give three pairs of enantiomers (10S,11R,13S)/(10R,11S,13R)-colletotrichindole A, (10R,11R,13S)/(10S,11S,13R)-colletotrichindole C, and (9S,10S)/(9R,10R)-colletotrichdiol A, respectively. The chemical structures of seven undescribed compounds and the known compounds, (-)-isoalternatine A, and (+)-alternatine A were determined using a combination of NMR, MS, X-ray diffraction, ECD calculations, and/or chemical synthesis. All possible enantiomers of colletotrichindoles A-E were synthesized and used to determine the absolute configurations of the natural products by comparing their spectroscopic data and HPLC retention times on a chiral column. In addition, the X-ray crystal structures of the known compounds (-)-isoalternatine A and (+)-alternatine A were also obtained to confirm their absolute configurations. (10S,11R,13S)-Colletotrichindole A, colletotrichindole B, and (+)-alternatine A significantly reduced triglyceride levels in 3T3-L1 cells with EC50 values of 5.8, 9.0, and 1.3 µM, respectively.

Lentinuses A-B, two alkaloids from the marine-derived fungus Lentinus sajor-caju with potent anti-pulmonary fibrosis activity.

By adding natural amino acids into the medium as sole nitrogen source, twenty-four compounds, including two new alkaloids lentinuses A-B (1-2) with a rare oxazinone core in marine natural products, one new natural product 3-acetamido-4-phenylfurazan (3), 9ß-ergosterol (22) were firstly discovered from a marine fungus, and twenty known compounds (4-21, 23-24) were isolated from the marine-derived fungus Lentinus sajor-caju. The chemical structures of all these compounds were elucidated by HRMS, NMR spectroscopy and X-ray diffraction. Compounds 1-24 were evaluated for their inhibitory activity against TGF-ß1-induced collagen accumulation in human fetal lung fibroblasts (HFL1). Compounds 2, 3, 12, 22, and 23 showed potent activity against TGF-ß1-induced collagen accumulation and low toxicity to HFL1 cells. The binding mode of lentinus B (2) with TGF-ß1 receptor was then performed by using Schrödinger software, and the result showed that lentinus B possesses a strong binding force such as hydrogen bonding and hydrophobic interactions to the protein, which may provide a theoretical basis to design more potent anti-fibrotic drugs in the future.

Indole alkaloids fusarindoles A-E from marine-derived fungus Fusarium equiseti LJ-1.

Five undescribed indole alkaloids, fusarindoles A-E, together with seven known compounds were obtained from the marine-derived fungus Fusarium equiseti LJ-1. Their chemical structures and absolute configurations were determined by comprehensive analysis of the NMR, HRMS, UV, IR, ECD calculation and single-crystal X-ray diffraction data. The possible biosynthetic pathways of fusarindoles C-E were proposed. The cytotoxicities of eleven compounds, including fusarindoles A-E and six known compounds, against five human cancer cell lines A549, CNE2, SUNE1, HepG2 and QGY7701 were evaluated.

ß-Carboline Alkaloids From the Deep-Sea Fungus Trichoderma sp. MCCC 3A01244 as a New Type of Anti-pulmonary Fibrosis Agent That Inhibits TGF-ß/Smad Signaling Pathway.

Pulmonary fibrosis is a scarring disease of lung tissue, which seriously threatens human health. Treatment options are currently limited, and effective strategies are still lacking. In the present study, 25 compounds were isolated from the deep-sea fungus Trichoderma sp. MCCC 3A01244. Among them, two ß-carboline alkaloids, trichocarbolines A (1) and C (4) are new compounds. The chemical structures of these compounds were elucidated based on their HRESIMS, 1D and 2D NMR spectra, optical rotation calculation, and comparisons with data reported in the literature. Trichocarboline B [(+)- and (-)-enantiomers] had previously been synthesized, and this is its first report as a natural product. Their anti-pulmonary fibrosis (PF) activity and cytotoxicity were investigated. Compounds 1, 11, and 13 strongly inhibited TGF-ß1-induced total collagen accumulation and showed low cytotoxicity against the HFL1 cell line. Further studies revealed compound 1 inhibited extracellular matrix (ECM) deposition by downregulating the expression of protein fibronectin (FN), proliferating cell nuclear antigen (PCNA), and α-smooth muscle actin (α-SMA). Mechanistic study revealed that compound 1 decreased pulmonary fibrosis by inhibiting the TGF-ß/Smad signaling pathway. As a newly identified ß-carboline alkaloid, compound 1 may be used as a lead compound for developing more efficient anti-pulmonary fibrosis agents.

Exophilone, a Tetrahydrocarbazol-1-one Analogue with Anti-Pulmonary Fibrosis Activity from the Deep-Sea Fungus Exophiala oligosperma MCCC 3A01264.

A new compound, exophilone (1), together with nine known compounds (2-10), were isolated from a deep-sea-derived fungus, Exophiala oligosperma. Their chemical structures, including the absolute configuration of 1, were elucidated using nuclear magnetic resonance (NMR) spectroscopy, high-resolution electrospray ionization mass spectroscopy (HRESIMS), and electronic circular dichroism (ECD) calculation. Compounds were preliminarily screened for their ability to inhibit collagen accumulation. Compounds 1, 4, and 7 showed weaker inhibition of TGF-ß1-induced total collagen accumulation in compared with pirfenidone (73.14% inhibition rate). However, pirfenidone exhibited cytotoxicity (77.57% survival rate), while compounds 1, 4, and 7 showed low cytotoxicity against the HFL1 cell line. Particularly, exophilone (1) showed moderate collagen deposition inhibition effect (60.44% inhibition rate) and low toxicity in HFL1 cells (98.14% survival rate) at a concentration of 10 µM. A molecular docking study suggests that exophilone (1) binds to both TGF-ß1 and its receptor through hydrogen bonding interactions. Thus, exophilone (1) was identified as a promising anti-pulmonary fibrosis agent. It has the potential to be developed as a drug candidate for pulmonary fibrosis.

Monascuslactams A-D, cytotoxic γ-lactams from marine fungus Monascus albidus BB3.

Amino acid-directed strategy becomes an efficient way to explore the alkaloids' biosynthetic potential of marine fungi. The metabolites of marine fungus Monascus albidus BB3 were regulated obviously when cultured in GPY medium supplemented with L-tryptophan, L-phenylalanine, D,L-methionine, L-threonine, L-lysine, L-serine and L-valine. Four new γ-lactams, monascuslactams A-D (1-4), together with two known compounds pulchellalactam (5) and O-acetylperlolyrine (6) were obtained. Their structures were determined by comprehensive analysis on the 1 D and 2 D NMR, HRESIMS, UV and IR data, and their absolute configurations were assigned by the experimental and calculated ECD data analysis. Compounds 3, 4 and 6 showed moderate cytotoxicity against human cancer cell lines SUNE1, HepG2, QGY7701, GLC82, HCT116 and MDA-MB-231.

Biotransformations of anthranilic acid and phthalimide to potent antihyperlipidemic alkaloids by the marine-derived fungus Scedosporium apiospermum F41-1.

A new diphenylamine derivative, scediphenylamine A (1), together with six phthalimide derivatives (2-7) and ten other known compounds (8-17) were obtained from the marine-derived fungus Scedosporium apiospermum F41-1 fed with synthetically prepared anthranilic acid and phthalimide. The structure and absolute configuration of the new compound were determined by HRMS, NMR, and X-ray crystallography. Evaluation of their lipid-lowering effect in 3T3-L1 adipocytes showed that scediphenylamine A (1), N-phthaloyl-tryptophan-methyl ester (4), 5-(1,3-dioxoisoindolin-2-yl) pentanamide (5), perlolyrine (10) and flazine (11) significantly reduced triglyceride level in 3T3-L1 cells by inhibiting adipogenic differentiation and synthesis with the EC50 values of 4.39, 2.79, 3.76, 0.09, and 4.52 µM, respectively. Among them, perlolyrine (10) showed the most potent activity, making it a candidate for further development as a potential agent to treat hyperlipidemia.

Phomaligols F-I, polyoxygenated cyclohexenone derivatives from marine-derived fungus Aspergillus flavus BB1.

By tracing the 13C NMR resonances for carbonyls and enols, four new oxidized phomaligol derivatives, phomaligols F-I (1-4), along with seven known compounds (5-11) were isolated from the culture of the fungus Aspergillus flavus BB1 isolated from the marine shellfish Meretrix meretrix collected on Hailing Island, Yangjiang, China. The chemical structures and the absolute configurations of the new compounds were elucidated by MS, NMR, ECD, optical rotation, and 13C NMR calculations. Compounds 1 and 2 represent the first examples of phomaligol derivatives that contain an unusual bicyclic skeleton. All isolated compounds were tested for their cytotoxic activity. Among them, sporogen-AO 1 (8) showed potent inhibitory activity against the cancer cell lines A549, H1299, SK-BR-3, and HCT116 with IC50 values of 0.13, 0.78, 1.19, and 1.32 µM, respectively. Phomaligol G (2) displayed cytotoxic activity against the A549 and H1299 cell lines with IC50 values of 46.86 and 51.87 µM respectively. Additionally, phomaligol H (3) demonstrated cytotoxic activity against the A549 cell line with an IC50 value of 65.53 µM. Mechanistic studies of compound 8 showed that it induced apoptosis of HCT116 cells in a dose-dependent manner.

Monalbidins A-E, Decalins with Potential Cytotoxic Activities from Marine Derived Fungus Monascus albidus BB3.

Five new decalins, monalbidins A-E (1, 2 and 7-9), together with 16 known compounds (3-6 and 10-21), were isolated from the AcOEt extract of marine derived fungus Monascus albidus BB3 cultured in GPY medium. Among the known compounds, 1-hydroxymonacolin L (11), dehydromonacolin J (15), 8-O-acetylmonacolin J (19) and O-acetylmonacolin K (21) were separated from natural sources for the first time. Their structures were determined by comprehensive analysis on the 1D and 2D NMR, HR-ESI-MS, UV and IR data, and their absolute configurations were assigned by experimental and calculated ECD data, and X-ray single-crystal diffraction analysis. Monalbidins C and D (7 and 8), monacolin K methyl ester (13), dehydromonacolin L (14), dehydromonacolin K (16), monacolin K (20) and O-acetylmonacolin K (21) showed moderate cytotoxicity against human cancer cell lines SUNE1, HepG2, QGY7701, HCT116 and MDA-MB-231.

A pair of novel bisindole alkaloid enantiomers from marine fungus Fusarium sp. XBB-9.

A preliminary research on the marine fungus Fusarium sp. XBB-9 resulted in a pair of novel bisindole alkaloid enantiomers, (+)- and (-)-fusaspoid A (1a/1b) and 12 diverse compounds. One strain many compound (OSMAC) method was used to enhance as many biosynthetic pathways as possible. The structures of the compounds were elucidated by spectroscopic analysis, and the absolute configuration of 1a was determined by X-ray single-crystal diffraction analysis. Compounds 1a and 1b were tested for cytotoxic activity against HCT-15, RKO cell lines, but were inactive. Compounds 1a and 1b were the first example of bisindole alkaloids isolated from fungus Fusarium sp. XBB-9.

Reactive oxygen species altering the metabolite profile of the marine-derived fungus Dichotomomyces cejpii F31-1.

To investigate the influence of reactive oxygen species (ROS) on the secondary metabolites of the marine-derived fungus Dichotomomyces cejpii F31-1, hydrogen peroxide (H2O2) was added to the GPY culture medium. The HPLC chromatogram of the EtOAc extract of the culture broth was distinct from that of the H2O2 free GPY medium. Further study of the metabolites in the GPY medium with H2O2 resulted in the discovery of eight known compounds. Among them, (22E)-5α, 8α-epidioxyergosta-6, 22-dien-3ß-ol (2) and ergosta-4,6,8(14),22-tetraene-3-one (3) were present in the highest concentration, while ergosterol and diketopiperazines are abundant in the H2O2 free medium. Additionally, a new compound, dichocetide D (1) containing a chlorine element and a known ergosterol (10) were isolated from the H2O2 free medium. (22E)-5α, 8α-epidioxyergosta-6, 22-dien-3ß-ol (2) exhibited moderate cytotoxic activity against human prostate cancer cell line LNCaP-C4-2B.

l-Tryptophan Induces a Marine-Derived Fusarium sp. to Produce Indole Alkaloids with Activity against the Zika Virus.

The effects of l-tryptophan supplementation on secondary metabolite production in the marine-derived fungus Fusarium sp. L1 were investigated by culturing the fungus in GPY medium with and without the amino acid. HPLC analysis of the products showed distinct metabolite profiles between the two cultures. The 1H NMR spectrum of the EtOAc extract of the culture supplemented with l-tryptophan displayed a series of characteristic aromatic proton signals (δH 6.50-8.50) and NH signals (δH 10.50-11.50) that were not observed in those from cultures not supplemented with l-tryptophan. Subsequently, 23 distinct indole alkaloids, including six new compounds, fusaindoterpenes A and B (1 and 2), fusariumindoles A-C (3-5), and (±)-isoalternatine A (6), together with 17 known compounds, were obtained from this culture. Fusaindoterpene A (1) contains a 6/9/6/6/5 heterocyclic system. Their chemical structures were determined by analysis of HRMS, NMR spectroscopy, optical rotation calculation, ECD calculation, and single-crystal X-ray diffraction data. Compounds 2, 9, and 15 displayed inhibitory activity against the Zika virus (ZIKV) in a standard plaque assay with EC50 values of 7.5, 4.2, and 5.0 µM, respectively, while not showing significant cell cytotoxicity against the A549 adenocarcinomic human alveolar basal epithelial cell line.

Potential Antidiabetic Fumiquinazoline Alkaloids from the Marine-Derived Fungus Scedosporium apiospermum F41-1.

Fumiquinazoline alkaloids have attracted much attention from medicinal and natural product chemists due to their interesting structures and biological potential. In this study, three new and 12 known fumiquinazoline alkaloids were isolated and characterized from the marine fungus Scedosporium apiospermum F41-1. The structures of the new compounds and their absolute configurations were determined using NMR spectroscopy, ECD, and OR calculations. The compounds were evaluated for their antidiabetic potential by determining their triglyceride-promoting activity using 3T3-L1 adipocytes. One of the new compounds, scequinadoline J (14), as well as scequinadolines D (9) and E (10), was found to promote triglyceride accumulation in 3T3-L1 cells. Scequinadoline D (9) demonstrated the most potent activity, with an EC50 value of 0.27 ± 0.03 µM. Quantitative polymerase chain reaction experiments suggested that scequinadoline D (9) acts through activation of the PPARγ pathway. It stimulated the mRNA expression of PPARγ, AMPKα, C/EBPα, LXRα, SCD-1, and FABP4. In addition, its triglyceride-promoting efficacy could be blocked by a double dose of the PPARγ antagonist GW9662. These results indicated that scequinadoline D (9) is a potent insulin sensitizer that targets adipocytes and may be useful for the treatment of type 2 diabetes mellitus after further investigation.

Monarubins A-C from the Marine Shellfish-Associated Fungus Monascus ruber BB5.

Three new compounds, monarubins A-C (1, 6 and 13), together with ten known compounds, including four alkaloids (2-5), two isocoumarins (7 and 8) and four polyketides (9-12), were isolated from marine shellfish-associated fungus Monascus ruber BB5. The structures were determined on the basis of the 1D and 2D NMR, MS, UV and IR data. The absolute configurations of compounds 3, 6 and 13 were determined by ECD calculations. The NMR data of compounds deoxyhydroxyaspergillic acid (3) and 2-hydroxy-6-(1-hydroxy-1-methylpropyl)-3-sec-buthylpyrazine (4) were first reported. All of the isolated compounds were evaluated for their cytotoxic activities against human nasopharyngeal carcinoma cell lines CNE1, CNE2, SUNE1 and HONE1 and hepatocellular carcinoma cell lines QGY7701 and HepG2. Monarubin B (6) displayed potent cytotoxicities against the cancer cell lines HepG2 and QGY7701 with IC50 values of 1.72 and 0.71 µΜ, respectively; lunatinin (7) showed moderate cytotoxic activities against the cancer cell lines HepG2, QGY7701 and SUNE1 with the IC50 values of 9.60, 7.12 and 28.12 µΜ, respectively.

Cytotoxic alkaloids from the marine shellfish-associated fungus Aspergillus sp. XBB-4 induced by an amino acid-directed strategy.

Eight different culture media were used to culture shellfish Panopea abbreviate associated fungus Aspergillus sp. XBB-4. In a glucose-peptone-yeast (GPY) culture medium supplied with amino acids, this fungus can produce chemodiversity metabolites. Four new alkaloids including three ß-carboline alkaloids, aspercarbolines A-C (1-3) and one piperazinedione, asperdione A (13) along with nine known compounds were isolated. The structures were elucidated mainly based on the NMR, MS, ECD and X-ray single-crystal diffraction data. The possible biosynthetic pathways of aspercarbolines A-C (1-3) were proposed. All compounds (1-13) were evaluated for their cytotoxicity against six cancer cell lines, including human nasopharyngeal carcinoma cell lines CNE1, CNE2, HONE1 and SUNE1, and human hepatocellular carcinoma cell lines hepG2 and QGY7701.

l-Phenylalanine Alters the Privileged Secondary Metabolite Production in the Marine-Derived Fungus Trichoderma erinaceum F1-1.

The effects of a single-amino-acid culture strategy on secondary metabolite production in the marine-derived fungus Trichoderma erinaceum F1-1 were investigated by culturing the fungus in GPY medium supplemented or not supplemented with l-phenylalanine. A suite of secondary metabolites, including seven terpenoids (1-7) and one polyketide (8), among which are four new compounds, harziandione A (1), cyclonerodiols A and B (3, 4), and trichodermaerin A (6), were isolated from the GPY medium without l-phenylanine, whereas 18 aromatic compounds (9-26), including six new compounds, trichoderolides A-F (9, 10, and 14-17), were isolated from the culture grown in the GPY medium with l-phenylalanine. The structures of the new compounds were determined by high-resolution mass spectrometry, NMR spectroscopic analysis, optical rotation calculations, chemical methods, and X-ray crystallography. Compounds 10, 12, 13, and 26 exhibited cytotoxic activities against MDA-MB-435 human melanocyte cancer cells. Compound 26 was cytotoxic to A549 adenocarcinomic human alveolar basal epithelial cells.

Exploration of Indole Alkaloids from Marine Fungus Pseudallescheria boydii F44-1 Using an Amino Acid-Directed Strategy.

The composition of the culture medium has great influence on the metabolite production of the marine fungus Pseudallescheria boydii F44-1. By adding amino acids to GPY culture medium, two new bisindole alkaloids, pseudboindoles A and B (1 and 2), together with 11 known indole alkaloids were isolated from the culture broth. Their structures were elucidated by comprehensive analysis of the NMR, MS, IR, and UV spectra. The 3,3'-cyclohexylidenebis(1H-indole) (3) showed cytotoxic activity against various cancer cell lines.

Linear Triquinane Sesquiterpenoids: Their Isolation, Structures, Biological Activities, and Chemical Synthesis.

Linear triquinane sesquiterpenoids represent an important class of natural products. Most of these compounds were isolated from fungi, sponges, and soft corals, and many of them displayed a wide range of biological activities. On account of their structural diversity and complexity, linear triquinane sesquiterpenoids present new challenges for chemical structure identification and total synthesis. 118 linear triquinane sesquiterpenoids were classified into 8 types, named types I⁻VIII, based on the carbon skeleton and the position of carbon substituents. Their isolation, structure elucidations, biological activities, and chemical synthesis were reviewed. This paper cited 102 articles from 1947 to 2018.

Polyketides and Alkaloids from the Marine-Derived Fungus Dichotomomyces cejpii F31-1 and the Antiviral Activity of Scequinadoline A against Dengue Virus.

In our continuous chemical investigation on the marine-derived fungus Dichotomomyces cejpii F31-1, two new polyketides dichocetides B-C (1, 2), two new alkaloids dichotomocejs E-F (3, 4), and three known fumiquinozalines: scequinadoline A (5), quinadoline A (6), and scequinadoline E (7) were discovered from the culture broth and the mycelium in the culture medium, by the addition of l-tryptophan and l-phenylalanine. Their chemical structures were established by one dimensional (1D), two dimensional (2D) nuclear magnetic resonance (NMR) and high resolution mass spectrometry (HR-MS) data. Among them, scequinadoline A (5) exhibited significant inhibitory activity against dengue virus serotype 2 production by standard plaque assay, equivalent to the positive control andrographlide. Scequinadoline A (5) possesses the potential for further development as a dengue virus inhibitor.