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.

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.

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.

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.

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.

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.

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.

Activation of dormant secondary metabolite production by introducing neomycin resistance into the deep-sea fungus, Aspergillus versicolor ZBY-3.

A new ultrasound-mediated approach has been developed to introduce neomycin-resistance to activate silent pathways for secondary metabolite production in a bio-inactive, deep-sea fungus, Aspergillus versicolor ZBY-3. Upon treatment of the ZBY-3 spores with a high concentration of neomycin by proper ultrasound irradiation, a total of 30 mutants were obtained by single colony isolation. The acquired resistance of the mutants to neomycin was confirmed by a resistance test. In contrast to the ZBY-3 strain, the EtOAc extracts of 22 of the 30 mutants inhibited the human cancer K562 cells, indicating that these mutants acquired a capability to produce antitumor metabolites. HPLC-photodiode array detector (PDAD)-UV and HPLC-electron spray ionization (ESI)-MS analyses of the EtOAc extracts of seven bioactive mutants and the ZBY-3 strain indicated that diverse secondary metabolites have been newly produced in the mutant extracts in contrast to the ZBY-3 extract. The followed isolation and characterization demonstrated that six metabolites, cyclo(D-Pro-D-Phe) (1), cyclo(D-Tyr-D-Pro) (2), phenethyl 5-oxo-L-prolinate (3), cyclo(L-Ile-L-Pro) (4), cyclo(L-Leu-L-Pro) (5) and 3ß,5α,9α-trihydroxy-(22E,24R)-ergosta-7,22-dien-6-one (6), were newly produced by the mutant u2n2h3-3 compared to the parent ZBY-3 strain. Compound 3 was a new compound; 2 was isolated from a natural source for the first time, and all of these compounds were also not yet found in the metabolites of other A. versicolor strains. Compounds 1-6 inhibited the K562 cells, with inhibition rates of 54.6% (1), 72.9% (2), 23.5% (3), 29.6% (4), 30.9% (5) and 51.1% (6) at 100 µg/mL, and inhibited also other human cancer HL-60, BGC-823 and HeLa cells, to some extent. The present study demonstrated the effectiveness of the ultrasound-mediated approach to activate silent metabolite production in fungi by introducing acquired resistance to aminoglycosides and its potential for discovering new compounds from silent fungal metabolic pathways. This approach could be applied to elicit the metabolic potentials of other fungal isolates to discover new compounds from cryptic secondary metabolites.

Nine new and five known polyketides derived from a deep sea-sourced Aspergillus sp. 16-02-1.

Nine new C9 polyketides, named aspiketolactonol (1), aspilactonols A-F (2-7), aspyronol (9) and epiaspinonediol (11), were isolated together with five known polyketides, (S)-2-(2'-hydroxyethyl)-4-methyl-γ-butyrolactone (8), dihydroaspyrone (10), aspinotriol A (12), aspinotriol B (13) and chaetoquadrin F (14), from the secondary metabolites of an Aspergillus sp. 16-02-1 that was isolated from a deep-sea sediment sample. Structures of the new compounds, including their absolute configurations, were determined by spectroscopic methods, especially the 2D NMR, circular dichroism (CD), Mo2-induced CD and Mosher's 1H NMR analyses. Compound 8 was isolated from natural sources for the first time, and the possible biosynthetic pathways for 1-14 were also proposed and discussed. Compounds 1-14 inhibited human cancer cell lines, K562, HL-60, HeLa and BGC-823, to varying extents.

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.

A novel hemiacetal from the marine-derived fungus Penicillium citrinum.

A novel hemiacetal, citrinacetal (1) was isolated from a marine-derived fungus Penicillium citrinum by column chromatography on silica gel, Sephadex LH-20 and semi-preparative HPLC. Its structure and stereochemistry was established on the basis of HR-ESI-MS, 1D and 2D NMR spectroscopic methods. The NMR spectrum showed this compound exists in solution as a mixture of two stereoisomers. The cytotoxic effect of compound 1 was evaluated in A-549, HL-60, HeLa, and K562 cancer cell lines. However, compound 1 only displayed weak cytotoxic activity on HL-60 cell, with IC50 value 77.4 micromol x L(-1).

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.

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.

Three new dioxopiperazine metabolites from a marine-derived fungus Aspergillus fumigatus Fres.

Three new dioxopiperazine metabolites (1-3), together with two known compounds, N-acetyltyramine (4) and cyclo-(Ala-Val) (5), were isolated from a marine-derived fungus Aspergillus fumigatus Fres. Their structures were established by spectroscopic methods. Their cytotoxic activities against the K562 cell line were preliminarily evaluated by the sulphorhodamine B (SRB) method.

Two new hetero-spirocyclic gamma-lactam derivatives from marine sediment-derived fungus Aspergillus sydowi D2-6.

Two new hetero-spirocyclic gamma-lactams, azaspirofurans A (1) and B (2), had been isolated from a marine sediment-derived fungus Aspergillus sydowi D2-6. Their structures were determined by the chemical evidence and spectral analyses. Compound 1 exhibited cytotoxicity against A549 cell line with the IC50 value of 10 microM by MTT method.

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.

2-Hydroxydiplopterol, a new cytotoxic pentacyclic triterpenoid from the halotolerant fungus Aspergillus variecolor B-17.

A new hopane type pentacyclic triterpenoid, 2-hydroxydiplopterol (1) has been isolated from the metabolites produced by the halotolerant fungal strain Aspergillus variecolor B-17. The structure of 1 was determined by spectroscopic methods and single crystal X-Ray diffraction analysis. 2-Hydroxydiplopterol (1) exhibited cytotoxicity against K562 cells with an IC50 value of 22 microM.

Cytotoxic and antioxidative phenolic compounds from the traditional Chinese medicinal plant, Myristica fragrans.

Two new phenolic compounds were isolated from the fruits of Myristica fragrans and their structures were elucidated as (-)-1-(2,6-dihydroxyphenyl)-9-[4-hydroxy-3-(p-menth-1-en-8-oxy)-phenyl]-1-nonanone ( 1) and (7 R,8 R)-7,8-dihydro-7-(3,4-dihydroxyphenyl)-3'-methoxy-8-methyl-1'-( E-propenyl)benzofuran (2). In addition, the absolute configuration of (+)-Delta8'-7-acetoxy-3,4,3',5'-tetramethoxy-8- O-4'-neolignan (3) was determined for the first time through spectroscopic and chemical methods. Their antioxidative activities against 2,2-diphenyl-1-picrylhydrazyl radical and cytotoxicity against K-562 cells were tested, and (7 S,8 S,7' R,8' S)-4,5'-dihydroxy-3,3'-dimethoxy-7,7'-epoxylignan (4) showed the corresponding activities with IC(50) values of 39.4 and 2.11 microM, respectively.