Isolation and Structure Elucidation of New Metabolites from the Mariana-Trench-Associated Fungus Aspergillus sp. SY2601.

Fungi are important resource for the discovery of novel bioactive natural products. This study investigated the metabolites produced by Mariana-Trench-associated fungus Aspergillus sp. SY2601 in EY liquid and rice solid media, resulting in the isolation and structure determination of 28 metabolites, including five new compounds, asperindopiperazines A-C (1-3), 5-methoxy-8,9-dihydroxy-8,9-deoxyaspyrone (21), and 12S-aspertetranone D (26). Structures of the new compounds were elucidated based on extensive NMR spectral analyses, HRESIMS data, optical rotation, ECD, and 13C NMR calculations. The new compound 12S-aspertetranone D (26) exhibited antibacterial activity against both methicillin-resistant Staphylococcus aureus and Escherichia coli with MIC values of 3.75 and 5 µg/mL, respectively.

Streptonaphthyridine A, a new naphthyridine analogue with antiproliferative activity against human glioma cells from mariana trench-associated actinomycete Streptomyces sp. SY2111.

A new naphthyridine analogue, named streptonaphthyridine A (1), together with eight previously reported compounds (2-9), were isolated from a Mariana Trench sediment-associated actinomycete Streptomyces sp. SY2111. Planar structure of streptonaphthyridine A was established by analyses of its HRESIMS data and extensive NMR spectra and its absolute configuration was determined by a combination of single crystal X-ray diffraction analysis and optical rotation calculations. Streptonaphthyridine A (1) had antiproliferative activity against human glioma U87MG and U251 cells with IC50 values of 7.9 ± 1.3 and 13.4 ± 2.7 µM, respectively, and the known compound monomethylsulochrin (7) showed more potent activity with IC50 values of 0.6 ± 0.1 µM for U87MG cells and 0.1 ± 0.0 µM for U251 cells.

New Hygrocins K-U and Streptophenylpropanamide A and Bioactive Compounds from the Marine-Associated Streptomyces sp. ZZ1956.

Marine-derived Streptomyces actinomycetes are one of the most important sources for the discovery of novel bioactive natural products. This study characterized the isolation, structural elucidation and biological activity evaluation of thirty compounds, including twelve previously undescribed compounds, namely hygrocins K-U (5-13, 17 and 18) and streptophenylpropanamide A (23), from the marine-associated actinomycete Streptomyces sp. ZZ1956. Structures of the isolated compounds were determined by a combination of extensive NMR spectroscopic analyses, HRESIMS data, the Mosher's method, ECD calculations, single crystal X-ray diffraction and comparison with reported data. Hygrocins C (1), D (2), F (4), N (8), Q (11) and R (12), 2-acetamide-6-hydroxy-7-methyl-1,4-naphthoquinone (22), echoside C (27), echoside A (28) and 11,11'-O-dimethylelaiophylin (30) had antiproliferative activity (IC50: 0.16-19.39 µM) against both human glioma U87MG and U251 cells with hygrocin C as the strongest active compound (IC50: 0.16 and 0.35 µM, respectively). The analysis of the structure-activity relationship indicated that a small change in the structures of the naphthalenic ansamycins had significant influence on their antiglioma activities. Hygrocins N (8), O (9), R (12), T (17) and U (18), 2-amino-6-hydroxy-7-methyl-1,4-naphthoquinone (21), 2-acetamide-6-hydroxy-7-methyl-1,4-naphthoquinone (22), 3'-methoxy(1,1',4',1″-terphenyl)-2',6'-diol (26), echoside C (27) and echoside A (28) showed antibacterial activity against methicillin-resistant Staphylococcus aureus and Escherichia coli with MIC values of 3-48 µg/mL.

Cytotoxic metabolites from the marine-associated Streptomyces sp. ZZ1944.

Marine-derived actinomycetes from the genus Streptomycete have a huge potential for the production of metabolites with structural and bioactive uniqueness and diversity. This study described the isolation and structural elucidation of twenty metabolites, including seven previously unreported compounds galbonolide H, galbonolide I, streptophenylpropionic acid A, treptophenylpropyl ester A, streptophenvaleramide A, seco-geldanamycin A and streptorapamycin A, from the marine-associated Streptomycete sp. ZZ1944. Structures of the isolated compounds were elucidated by a combination of extensive NMR spectroscopic analyses, HRESIMS data, optical rotation and ECD calculations. The structure of galbonolide H was also confirmed by a single crystal X-ray diffraction. Both autolytimycin and seco-geldanamycin A showed potent activity against the proliferation of glioma, lung cancer, colorectal cancer and breast cancer cells. Autolytimycin blocked cell cycle of glioma cells and seco-geldanamycin A induced apoptosis of glioma cells.

Talaromydien a and talaroisocoumarin A, new metabolites from the marine-sourced fungus Talaromyces sp. ZZ1616.

New talaromydien A (1) and talaroisocoumarin A (2), together with nine known compounds (3 - 11), were isolated from a culture of the marine-derived Talaromyces sp. ZZ1616 in potato dextrose broth medium. Structures of the new compounds were elucidated based on their HRESIMS data, NMR spectroscopic analyses, the modified Mosher's method, ECD, 13C NMR and optical rotation calculations. Talaroisocoumarin A showed antimicrobial activities with MIC values of 36.0 µg/mL against methicillin-resistant Staphylococcus aureus, 32.0 µg/mL against Escherichia coli, and 26.0 µg/mL against Candida albicans.

Multitask CapsNet: An Imbalanced Data Deep Learning Method for Predicting Toxicants.

Drug development has a high failure rate, with safety properties constituting a considerable challenge. To reduce risk, in silico tools, including various machine learning methods, have been applied for toxicity prediction. However, these approaches often confront a serious problem: the training data sets are usually biased (imbalanced positive and negative samples), which would result in model training difficulty and unsatisfactory prediction accuracy. Multitask networks obtained significantly better predictive accuracies than single-task methods, and capsule neural networks showed excellent performance in sparse data sets in previous studies. In this study, we developed a new multitask framework based on a capsule neural network (multitask CapsNet) to measure 12 different toxic effects simultaneously. We found that multitask CapsNet excelled in toxicity prediction and outperformed many other computational approaches using the multitask strategy. Only after training on biased data sets did multitask CapsNet achieve significantly improved prediction accuracy on the Tox21 Data Challenge, which gave the largest ratio of highest accuracy (8/12) among compared models. Our model gave a prediction accuracy of 96.6% for the target NR.PPAR.gamma, whose ratio of negative to positive samples was up to 36:1. These results suggested that multitask CapsNet could overcome the bias problems and would provide a novel, accurate, and efficient approach for predicting the toxicities of compounds.

Evaluation of the antiproliferative activity of 106 marine microbial metabolites against human lung cancer cells and potential antiproliferative mechanism of purpuride G.

A total of 106 marine microbial metabolites were evaluated for their antiproliferative activity against human lung cancer cells. Results showed that 23 compounds exhibited activity in inhibiting the proliferation of A549 and H157 cells with IC50 values ranging from 1.5 to 48.2 µM. Pyrrospirone F, chrysophanol, physcion, and purpuride G are the four most active compounds with IC50 values of 1.5-7.3 µM. Further investigation of purpuride G (a newly discovered sesquiterpene lactone) demonstrated its potent antiproliferative activity against six different lung cancer cells of A549, H157, H460, H1299, H1703, and PC9 with IC50 values of 2.1-3.3 µM. The antiproliferative activity of purpuride G against cancer cells is related to block cell cycle, induce apoptosis through regulating the apoptotic proteins Bcl-2 and Bax, and inhibit glycolysis by downregulating two key glycolytic enzymes of hexokinase 2 and pyruvate kinase M2.

A small natural molecule CADPE kills residual colorectal cancer cells by inhibiting key transcription factors and translation initiation factors.

Residual disease is the major cause for colorectal cancer (CRC) relapse. Herein, we explore whether and how a natural molecule CADPE killed heterogenic populations in a panel of CRC cell lines with KRAS/BRAF mutations that are natively resistant to EGFR- or VEGFR-targeted therapy, without sparing persistent cells, a reservoir of the disease relapse. Results showed that CADPE killed the tumor bulk and residual cells in the panel of CRC cell lines, rapidly inactivated c-Myc, STAT3, and NF-κB, and then decreased the protein levels of key signaling molecules for CRC, such as ß-catenin, Notch1, and the nodes of mTOR pathways; eukaryotic translation initiation factors (eIF4F); anti-apoptotic proteins (Bcl-xl, Mcl-1, and survivin); and stemness-supporting molecules (CD133, Bim-1, and VEGF). In terms of mechanism of action, concurrent downregulation of Mcl-1, Bcl-xl, and survivin was necessary for CADPE to kill CRC bulk cells, while additional depletion of CD133 and VEGF proteins was required for killing the residual CRC cells. Moreover, the disabled c-Myc, STAT3, NF-κB, and eIF4F were associated with the broadly decreased levels of anti-apoptosis proteins and pro-stemness proteins. Consistently, CADPE suppressed CRC tumor growth associated with robust apoptosis and depleted levels of c-Myc, STAT3, NF-κB, eIF4F, anti-apoptotic proteins, and pro-stemness proteins. Our findings showed the promise of CADPE for treating CRC and suggested a rational polytherapy that disables c-Myc, STAT3, NF-κB, and eIF4F for killing CRC residual disease.

Bioactive Alkaloids from the Actinomycete Actinoalloteichus sp. ZZ1866.

The new alkaloids marinacarbolines E-Q (1-10, 12-14), caerulomycin N (15), and actinoallonaphthyridine A (16), together with the known marinacarboline C (11) and cyanogramide (17), were isolated from the actinomycete Actinoalloteichus sp. ZZ1866. The structures of the isolated compounds were elucidated based on their HRESIMS data, extensive NMR spectroscopic analyses, Mosher's method, ECD calculations, single-crystal X-ray diffraction analysis, and chemical degradation studies. Marinacarbolines E-L (1-8) share an indole-pyridone-imidazole tetracyclic skeleton, which is the first example of this kind of skeleton. Caerulomycin N (15) and cyanogramide (17) exhibited cytotoxic activity against both human glioma U251 and U87MG cells with IC50 values of 2.0-7.2 µM. Marinacarbolines E (1), G (3), I (5), and M (9) showed cytotoxic activity against U87MG cells with IC50 values of 2.3-8.9 µM.

New Antifungal Metabolites from the Mariana Trench Sediment-Associated Actinomycete Streptomyces sp. SY1965.

New streptothiazolidine A (1), streptodiketopiperazines A (2) and B (3), and (S)-1-(3-ethylphenyl)-1,2-ethanediol (4), together with eight known compounds (5-12), were isolated from the Mariana Trench sediment-associated actinomycete Streptomyces sp. SY1965. The racemic mixtures of (±)-streptodiketopiperazine (2 and 3) and (±)-1-(3-ethylphenyl)-1,2-ethanediol (4 and 5) were separated on a chiral high-performance liquid chromatography (HPLC) column. Structures of the new compounds were elucidated by their high-resolution electrospray ionization mass spectroscopy (HRESIMS) data and extensive nuclear magnetic resonance (NMR) spectroscopic analyses. Streptothiazolidine A is a novel salicylamide analogue with a unique thiazolidine-contained side chain and its absolute configuration was established by a combination of nuclear Overhauser effect spectroscopy (NOESY) experiment, electronic circular dichroism (ECD) and 13C NMR calculations. New streptothiazolidine A (1) and streptodiketopiperazines A (2) and B (3) showed antifungal activity against Candida albicans with MIC values of 47, 42, and 42 g/mL, respectively.

Bioactive Metabolites from the Mariana Trench Sediment-Derived Fungus Penicillium sp. SY2107.

Mariana Trench sediments are enriched in microorganisms, however, the structures and bioactivities of their secondary metabolites are not very known. In this study, a fungus Penicillium sp. SY2107 was isolated from a sample of Mariana Trench sediment collected at a depth of 11000 m and an extract prepared from the culture of this fungus in rice medium showed antimicrobial activities. Chemical investigation on this active extract led to the isolation of 16 compounds, including one novel meroterpenoid, named andrastone C. Structure of the new compound was elucidated based on high-resolution electrospray ionization mass spectroscopy (HRESIMS) data, extensive nuclear magnetic resonance (NMR) spectroscopic analyses and a single crystal X-ray diffraction. The crystal structure of a known meroterpenoid andrastone B was also reported in this study. Both andrastones B and C exhibited antimicrobial activities against methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli, and Candida albicans with minimum inhibitory concentration (MIC) values in a range from 6 to 13 g/mL.

A rare diketopiperazine glycoside from marine-sourced Streptomyces sp. ZZ446.

Two diketopiperazines were isolated from a culture of the marine-derived actinomycete Streptomyces sp. ZZ446. Their structures were elucidated as maculosin (1) and maculosin-O-α-L-rhamnopyranoside (2) based on their NMR and HRESIMS data, specific rotation, and chemical degradation. Maculosin-O-α-L-rhamnopyranoside (2) is a new diketopiperazine glycoside, a structural class not reported previously from the natural sources. Both compounds showed antimicrobial activity against methicillin-resistant Staphylococcus aureus, Escherichia coli, and Candida albicans with MIC values in a range from 26.0 to 37.0 µg/mL.[Formula: see text].

Novel cyclohexene and benzamide derivatives from marine-associated Streptomyces sp. ZZ502.

Three new compounds and the known benzamides of 2-acetamido-3-hydroxybenzamide, 2-amino-3-hydroxybenzamide, and 2-aminobenzamide were isolated from the culture of a marine actinomycete Streptomyces sp. ZZ502. Structures of the new compounds were determined as 3-amino-2-carboxamine-6(R)-chloro-4(R),5(S)-dihydroxy-cyclohex-2-en-1-one, 3-amino-2-carboxamine-4(S),6(S)-dihydroxy-cyclohex-2-en-1-one, and 3-hydroxy-2-propionamidobenzamide based on extensive NMR spectroscopical analysis, HRESIMS data, ECD calculation, and X-ray diffraction analysis. None of these isolated compounds showed activity in inhibiting the proliferation of glioma cells nor the growth of methicillin-resistant Staphylococcus aureus, Escherichia coli, and Candida albicans.

Bioactive Penicipyrrodiether A, an Adduct of GKK1032 Analogue and Phenol A Derivative, from a Marine-Sourced Fungus Penicillium sp. ZZ380.

Penicipyrrodiether A, an adduct of GKK1032 analogue and phenol A derivative, was isolated from a culture of marine-associated fungus Penicillium sp. ZZ380 and represents the first example of this type of fungal metabolite. Its structure was elucidated by extensive spectroscopic analyses, including 1D- and 2D-NMR, HRESIMS, MS/MS, and electronic circular dichroism calculation as well as single-crystal X-ray diffraction. Penicipyrrodiether A showed antibacterial activity in inhibiting the growth of methicillin-resistant Staphylococcus aureus with a MIC value of 5.0 µg/mL. Its plausible pathway for biosynthesis has been proposed.

Peniciphenalenins A-F from the culture of a marine-associated fungus Penicillium sp. ZZ901.

Marine-derived fungi of the genus Penicillium represent a huge potential for synthesizing the secondary metabolites with structural and bioactive uniqueness and diversity. In this study, six previously undescribed compounds peniciphenalenins A-F and four known compounds (+)-sclerodin, (+)-scleroderolide, (+)-sclerodione, and physcion were isolated from the culture of a marine-derived fungus Penicillium sp. ZZ901. Structures of the isolated compounds were elucidated by a combination of extensive NMR spectroscopic analysis, HRESIMS data, optical rotation value, ECD calculation, and single crystal X-ray diffraction. Peniciphenalenins A-C are the second examples of the type of neoherqueinones. The possible biosynthetic route of nine phenalenone derivatives has been suggested. The known (+)-scleroderolide showed both antiproliferative activity against glioma cells with IC50 values of 23.24-37.26 µM and antibacterial activity in suppressing the growth of methicillin-resistant Staphylococcus aureus and Escherichia coli with MIC values of 7.0 and 9.0 µg/mL, respectively.

Anti-glioma Natural Products Downregulating Tumor Glycolytic Enzymes from Marine Actinomycete Streptomyces sp. ZZ406.

Marine natural products are important resources for discovering novel anticancer drugs. In this study, an extract prepared from the culture of a sea anemone-derived actinomycete Streptomyces sp. ZZ406 in soluble starch and casein-related liquid medium was found to have activity in inhibiting the proliferation of glioma cells and reducing the production of lactate in glioma cells. Chemical investigation of this active crude extract resulted in the isolation of four new compounds and seven known ones. Structures of the new compounds were determined by a combination of extensive NMR analyses, HRESIMS and MS-MS data, electronic circular dichroism calculation, chemical degradation, and Marfey's method. New compound 1 showed potent activity against the proliferation of different glioma cells with IC50 values of 4.7 to 8.1 µM, high selectivity index (>12.3 to 21.3), and good stability in human liver microsomes. Western blot analysis revealed that compound 1 remarkably downregulated the expressions of several important glioma glycolytic enzymes. The data from this study suggested that compound 1 might have potential as a novel anti-glioma agent to be further investigated.

Anti-glioma Efficacy and Mechanism of Action of Tripolinolate A from Tripolium pannonicum.

Tripolinolate A as a new bioactive phenolic ester was previously isolated from a halophyte of Tripolium pannonicum. However, the in vitro and in vivo anti-glioma effects and mechanism of tripolinolate A have not been investigated. This study has demonstrated that (1) tripolinolate A inhibited the proliferation of different glioma cells with IC50 values of 7.97 to 14.02 µM and had a significant inhibitory effect on the glioma growth in U87MG xenograft nude mice, (2) tripolinolate A induced apoptosis in glioma cells by downregulating the expressions of antiapoptotic proteins and arrested glioma cell cycle at the G2/M phase by reducing the expression levels of cell cycle regulators, and (3) tripolinolate A also remarkably reduced the expression levels of several glioma metabolic enzymes and transcription factors. All data together suggested that tripolinolate A had significant in vitro and in vivo anti-glioma effects and the regulation of multiple tumor-related regulators and transcription factors might be responsible for the activities of tripolinolate A against glioma.

Antiglioma pseurotin A from marine Bacillus sp. FS8D regulating tumour metabolic enzymes.

Pseurotin A was isolated from a culture of marine Bacillus sp. FS8D and showed to be active against the proliferation of four different glioma cells with IC50 values of 0.51-29.3 µM. It has been found that pseurotin A downregulated the expression of tumour glycolytic enzymes pyruvate kinase M2 (PKM2) and lactate dehydrogenase 5 (LDH5) and upregulated the expression of pyruvate dehydrogenase beta (PDHB), adenosine triphosphate synthase beta (ATPB) and cytochrome C (Cyto-C), the important regulators for tricarboxylic acid cycle and oxidative phosphorylation. The data suggested that targeting multiple metabolic enzymes might be one of the antiglioma mechanisms of pseurotin A.

A unique indolizinium alkaloid streptopertusacin A and bioactive bafilomycins from marine-derived Streptomyces sp. HZP-2216E.

Streptopertusacin A, a unique indolizinium alkaloid existing as a zwitterion, and six bafilomycins including two previously undescribed ones of 21,22-en-bafilomycin D and 21,22-en-9-hydroxybafilomycin D were isolated from a culture of the seaweed-derived Streptomyces sp. HZP-2216E. Structures of these isolated compounds were determined based on extensive NMR spectroscopic analyses, HRESIMS and MS-MS data. The stereochemical assignments were achieved by NOE information, chemical degradation, Marfey's method, and electronic circular dichroism (ECD) calculation. Streptopertusacin A is the first example of this type of indolizinium alkaloid from microorganisms and showed moderate activity against the growth of methicillin-resistant Staphylococcus aureus (MRSA). 21,22-en-bafilomycin D and 21,22-en-9-hydroxybafilomycin D had potent activities in inhibiting the proliferation of glioma cells and the growth of MRSA.

Anti-colorectal cancer effects of tripolinolate A from Tripolium vulgare.

Tripolinolate A (TLA) is recently identified as a new compound from a halophyte plant Tripolium vulgare and has been shown to have significant in vitro activity against the proliferation of colorectal cancer and glioma cells. This study was designed to further investigate the effects of TLA on the proliferation of human normal cells, and the apoptosis and cell cycle in colorectal cancer cells, and the growth of tumors in the colorectal cancer-bearing animals. The data obtained from this study demonstrated that: 1) TLA had much less cytotoxicity in the human normal cells than the colorectal cancer cells; 2) TLA remarkably induced apoptosis in the human colorectal cancer cells and blocked cell cycle at G2/M phase, and 3) TLA had significant anti-colorectal cancer activity in the tumor-bearing animals.