Identification of Gliotoxin isolated from marine fungus as a new pyruvate kinase M2 inhibitor.

Pyruvate kinase M2 (PKM2) functions as an important rate-limiting enzyme of aerobic glycolysis that is involved in tumor initiation and progression. However, there are few studies on effective PKM2 inhibitors. Gliotoxin is a marine-derived fungal secondary metabolite with multiple biological activities, including immunosuppression, cytotoxicity, and et al. In this study, we found that Gliotoxin directly bound to PKM2 and inhibited its glycolytic activity in a dose-dependent manner accompanied by the decreases in glucose consumption and lactate production in the human glioma cell line U87. Moreover, Gliotoxin suppressed tyrosine kinase activity of PKM2, leading to a dramatic reduction in Stat3 phosphorylation in U87 cells. Furthermore, Gliotoxin suppressed cell viability in U87 cells, and cytotoxicity of Gliotoxin on U87 cells was obviously augmented under hypoxia condition compared to normal condition. Finally, Gliotoxin was demonstrated to induce cell apoptosis of U87 cells and synergize with temozolomide. Our findings identify Gliotoxin as a new PKM2 inhibitor with anti-tumor activity, which lays the foundation for the development of Gliotoxin as a promising anti-tumor drug in the future.

New metabolites from a Mariana Trench-derived actinomycete Nocardiopsis sp. HDN 17-237.

One new ß,γ-butenoate derivative phenylbutenote (1), and one new α-pyrone nocapyrone T (2) were isolated from the deep-sea derived actinomycete Nocardiopsis sp. HDN 17-237. Their structures were elucidated by extensive HRMS, IR and NMR analyses. Among them, compound 1 is the first microbial natural products bearing a rare ß,γ-butenoate moiety, and compound 2 is the first α-pyrone isolated from strain of Mariana Trench. Compounds 1 and 2 were tested for antioxidant and antibacterial activities, while none of them showed significant activity.

Trichothecin Inhibits Cancer-Related Features in Colorectal Cancer Development by Targeting STAT3.

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that contributes to cancer progression through multiple processes of cancer development, which makes it an attractive target for cancer therapy. The IL-6/STAT3 pathway is associated with an advanced stage in colorectal cancer patients. In this study, we identified trichothecin (TCN) as a novel STAT3 inhibitor. TCN was found to bind to the SH2 domain of STAT3 and inhibit STAT3 activation and dimerization, thereby blocking STAT3 nuclear translocation and transcriptional activity. TCN did not affect phosphorylation levels of STAT1. TCN significantly inhibited cell growth, arrested cell cycle at the G0/G1 phase, and induced apoptosis in HCT 116 cells. In addition, the capacities of colony formation, migration, and invasion of HCT 116 cells were impaired upon exposure to TCN with or without IL-6 stimulation. In addition, TCN treatment abolished the tube formation of HUVEC cells in vitro. Taken together, these results highlight that TCN inhibits various cancer-related features in colorectal cancer development in vitro by targeting STAT3, indicating that TCN is a promising STAT3 inhibitor that deserves further exploration in the future.

N-Me-trichodermamide B isolated from Penicillium janthinellum, with antioxidant properties through Nrf2-mediated signaling pathway.

A new trichodermamide-like alkaloid, N-Me-trichodermamide B (compound 1), was isolated from a marine fungus Penicillium janthinellum HDN13-309. The structure and absolute configuration of compound 1 were determined by extensive NMR analysis and the modified Mosher's method. This new alkaloid exhibited cellular protection from the H2O2-induced oxidative damage, and the mechanism study revealed that this antioxidant activity was regulated through Nrf2-mediated signaling pathway in HaCaT human keratinocytes. In addition, the inhibitor of p38 abrogated compound 1-induced phosphorylation of p38, up-expression of HO-1, and the nuclear localization of Nrf2. As a result, it suggested that this new alkaloid-induced antioxidant signaling pathway might be initiated through activation of p38.

Exopisiod B and farylhydrazone C, two new alkaloids from the Antarctic-derived fungus Penicillium sp. HDN14-431.

Two new compounds, exopisiod B (1) and farylhydrazone C (2), together with two known compounds (3-4), were isolated from the Antarctic-derived fungus Penicillium sp. HDN14-431. Their structures including absolute configurations were elucidated by spectroscopic methods and TDDFT ECD calculations. The cytotoxicity and antimicrobial activities of all compounds were tested.

Rare Chromones from a Fungal Mutant of the Marine-Derived Penicillium purpurogenum G59.

Three new and rare chromones, named epiremisporine B (2), epiremisporine B1 (3) and isoconiochaetone C (4), along with three known remisporine B (1), coniochaetone A (5) and methyl 8-hydroxy-6-methyl-9-oxo-9H-xanthene-1-carboxylate (6) were isolated from a mutant from the diethyl sulfate (DES) mutagenesis of a marine-derived Penicillium purpurogenum G59. The structures of 2-4 including the absolute configurations were determined by spectroscopic methods, especially by NMR analysis and electronic circular dichroism (ECD) experiments in conjunction with calculations. The absolute configuration of the known remisporine B (1) was determined for the first time. Compounds 2 and 3 have a rare feature that has only been reported in one example so far. The compounds 1-6 were evaluated for their cytotoxicity against several human cancer cell lines. The present work explored the great potential of our previous DES mutagenesis strategy for activating silent fungal pathways, which has accelerated the discovery of new bioactive compounds.

Cladosins F and G, two new hybrid polyketides from the deep-sea-derived Cladosporium sphaerospermum 2005-01-E3.

Two new fungal hybrid polyketides, cladosins F (1) and G (2), with rare 6(3)-enamino-8,10-dihydroxy-tetraketide system were discovered from the deep-sea-derived fungus Cladosporium sphaerospermum 2005-01-E3 guided by OSMAC approach. Their structures were elucidated on the basis of comprehensive spectroscopic analyses, and cytotoxicity, antitubercular, anti-influenza A H1N1 virus, and NF-κB inhibitory activities were evaluated.

Three new polyketides from marine-derived fungus Aspergillus glaucus HB1-19.

Two new benzyl derivatives, aspergentisyl A (1) and aspergentisyl B (2), as well as one new naphthoquinone derivative, aspergiodiquinone (3), together with seven known prenylated benzaldehyde derivatives (4-10) were isolated from the marine-derived fungus Aspergillus glaucus HB1-19. The structures of these compounds were characterized based on 1D and 2D NMR spectra analyses and comparison with those reported in the literature. In addition, each isolate was tested for its 1,1-diphenyl-2-picrylhydrazyl radical-scavenging property and all these compounds except compound 3 exhibited strong radical-scavenging activity.

Three new cytochalasins from the marine-derived fungus Spicaria elegans KLA03 by supplementing the cultures with L- and D-tryptophan.

Three new cytochalasins Z(21) -Z(23) (1-3, resp.), together with five analogs, 4-8, were isolated from Spicaria elegans KLA03 by the OSMAC (one strain-many compounds) approach with adding L- and D-tryptophan during its cultivation. The structures of new cytochalasins were elucidated on the basis of comprehensive 1D- and 2D-NMR and HR-ESI-MS analyses. Cytochalasins Z(21) and Z(22) (1 and 2, resp.), and compound 5 showed cytotoxic activities against A-549 cell lines with IC(50) values of 8.2, 20.0, and 3.1 µM, respectively.

New cytotoxic metabolites from a deep-sea-derived fungus, Phialocephala sp., strain FL30r.

Two new sorbicillinoids, 1 and 2, together with a novel benzofuranone derivative named phialofurone (3), were isolated from a deep-sea sediment-derived fungus, Phialocephala sp. Their structures were established on the basis of spectroscopic data. All compounds displayed cytotoxic effects against P388 (IC(50) values of 11.5±1.4, 0.1±0.1, and 0.2±0.01 µM, resp.) and K562 (IC(50) values of 22.9±0.8, 4.8±0.3 and 22.4±0.9 µM, resp.) cell lines.

A new cytotoxic metabolite from a deep sea derived fungus, Phialocephala sp.

A new sesquiterpene hydroquinone (1) was isolated from a deep sea sediment derived fungus, Phialocephala sp.. Its structure and stereochemistry were established on the basis of spectroscopic data and optical rotation. This compound was tested for cytotoxicity against P388 (murine leukemia cell) and K562 (human leukemia cell) cell lines, and displayed strong cytotoxic effects with IC50 value of 0.16 and 0.05 micromol x L(-1), separately.

Penicacids E-G, three new mycophenolic acid derivatives from the marine-derived fungus Penicillium parvum HDN17-478.

Three new mycophenolic acid derivatives, penicacids E-G (1-3), together with three known analogues, mycophenolic acid (4), 4'-hydroxy-mycophenolic acid (5) and mycophenolic methyl ester (6), were isolated from a marine-derived fungus Penicillium parvum HDN17-478 from a South China Sea marine sediment sample. The structures of compounds 1-3 were elucidated by HRMS, NMR, and Mosher's method. Among them, compounds 1 and 2 were the first examples of mycophenolic acid analogs with a double bond at C-3'/C-4' position. The cytotoxicity of 1-6 was evaluated against the HCT-116, BEL-7402, MGC-803, SH-SY5Y, HO-8910 and HL-60 cell lines, and compounds 4 and 6 showed potent cytotoxicity with IC50 values ranging from 1.69 to 12.98 µmol·L-1.

Secondary metabolites from Antarctic marine-derived fungus Penicillium crustosum HDN153086.

A new polyene compound (1) and a new diketopiperazine (2), as well as three known compounds (3-5), were isolated from the Antarctic marine-derived fungus Penicillium crustosum HDN153086. The structures of 1-5 were deduced based on MS, NMR and TD-DFT calculations of specific ECD spectra. These compounds were evaluated for their cytotoxic activities against K562 cell line and only compound 2 exhibited cytotoxicity against K562 cell, with IC50 value of 12.7 µM.

Two new polyketides isolated from a diethyl sulphate mutant of marine-derived Penicillium purpurogenum G59.

Two new polyketides, purpurofuranone (1) and purpuropyranone (2), were isolated along with the known polyketides, cillifuranone (3) and taiwapyrone (4), from a mutant BD-3n-1 derived from the diethyl sulfate (DES) mutagenesis of a marine-derived Penicillium purpurogenum G59. The structures of 1 and 2 were elucidated by spectroscopic methods especially on the basis of X-ray diffraction and calculated optical rotations data. The plausible biosynthesis of 1 - 4 was also proposed and discussed. In preliminary MTT assay, 1 - 4 showed no notable inhibitory effects on the tested four human cancer cell lines.

Diversified Synthesis of Chiral Chromane-Containing Polyheterocyclic Compounds via Asymmetric Organocatalytic Cascade Reactions.

Two different organocatalytic cascade reaction pathways have been developed toward the diversified synthesis of chromane-containing polyheterocyclic compounds from the readily available starting materials. The application of Hantzsch ester is proposed to be the key to achieve the switch between these two different cascade reaction pathways, and then the electron-deficient 1-aza-1,3-butadienes could be used as the four-atom and two-carbon unit, respectively, to react with 2-hydroxy cinnamaldehydes in a highly regio- and stereocontrolled manner. On the basis of larger-scale synthesis, further transformations of the obtained products have also been realized, leading to cycloadducts with high structural and stereogenic complexity bearing five stereogenic centers, and one is a tetrasubstituted stereocenter.

Organocatalytic Diversity-Oriented Asymmetric Synthesis of Structurally and Stereochemically Complex Heterocycles.

An asymmetric organocatalytic direct arylation approach to construct arylated quaternary stereogenic centers with a catalyst loading of 1 mol % is reported. The formation of the hemiketal moiety in stabilizing the hydroquinone intermediate proves to be important in leading to hydroquinone products instead of oxidation quinone products obtained in previously reported methods. A series of structurally and stereochemically complex heterocyclic frameworks are obtained, including spiro-, dispiro-, fused, and bridged heterocycles.

Two new metabolites with cytotoxicities from deep-sea fungus, Aspergillus sydowi YH11-2.

Two new compounds, 2, 3, 5-trimethyl-6-(3-oxobutan-2-yl)-4H-pyran-4-one (1) and (2R)-2, 3- dihydro-7-hydroxy-6, 8-dimethyl-2-[(E)-prop-1-enyl] chromen-4-one (2), together with six known compounds (3-8), were isolated from a deep-sea fungus, identified as Aspergillus sydowi, by a bioassay-guided method. Their structures were elucidated by spectroscopic methods and the cytotoxicities were evaluated by SRB method.

Four butenolides are novel cytotoxic compounds isolated from the marine-derived bacterium, Streptoverticillium luteoverticillatum 11014.

Four known butenolides were isolated from the ethyl acetate extracts of the culture broth of the marine-derived bacterium, Streptoverticillium luteoverticillatum, by bioassay-guided fractionation. The structures were identified on the basis of spectral data. The absolute configuration of compound (1) was determined by CD spectrum for the first time. Compounds 1-4 showed in vitro cytotoxicity against the murine lymphoma P388 and human leukemia K562 cell lines. This is the first report on the isolation of butenolides from the marine bacterium, Streptoverticillium luteoverticillatum, and their cytotoxic activities.

Unprecedented citrinin trimer tricitinol B functions as a novel topoisomerase IIα inhibitor.

Fifteen citrinin derivatives (1-4, 6-16), including two unprecedented citrinin trimers tricitrinols A (3) and B (4), were isolated from Penicillium citrinum HGY1-5. The six-membered ring A system is essential for the cytotoxicity of active dimers (1, 2, and 5) and trimers (3 and 4). Tricitrinol B (4) showed extensive cytotoxicity in 17 tumor cells with comparable low-micromolar IC(50) values (1-10 µM) and potential antimultidrug resistance capabilities. Tricitrinol B (4) induced cell apoptosis in HL60 and HCT116 cells via mainly extrinsic pathways and G2/M arrest. Further antitumor mechanism study and computational docking analysis indicated that tricitrinol B (4) works as an intercalating topoisomerase IIα (topo IIα) poison, which inhibits the enzyme activity of topo IIα by interfering predominantly with the topo IIα-mediated poststrand-passage cleavage/religation equilibrium over with the prestrand-passage one and induced DNA damage. Tricitrinol B (4) represents a novel class of topo IIα-inhibitory skeletons for developing new chemotherapeutic agents.