2-Oxaspiro[4.5]decane and α-pyrenocine derivatives from the endophytic fungus Roussoella sp. PSU-H51.

One new 2-oxaspiro[4.5]decane, roussoellide, and one new α-pyrenocine, 2',3'-dihydropyrenocine A, together with nine known compounds including known arthropsolide A, and pyrenocines A and E, were obtained from the culture broth of the endophytic fungus Roussoella sp. Their structures were determined using spectroscopic data. The absolute configuration of known arthropsolide A was assigned on the basis of X-ray diffraction data using Cu Kα radiation. Known pyrenocine A displayed weak cytotoxic activity against breast cancer (MCF-7) cells with an IC50 value of 27.1 µM and weak antifungal activity against Microsporum gypseum SH-MU-4 with an MIC value of 615.2 µM.[Formula: see text].

Inhibition of CFTR-mediated intestinal chloride secretion by a fungus-derived arthropsolide A: Mechanism of action and anti-diarrheal efficacy.

Secretory diarrhea is one of the most common types of diarrhea with high morbidity and mortality. Previous studies showed that inhibition of cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channels alleviated fluid loss in secretory diarrheas. This study aimed to identify novel CFTR inhibitors from fungal metabolites and explore its underlying mechanisms and potential utility in secretory diarrheas. Electrophysiological analyses in human intestinal epithelial (T84) cells were performed to investigate the effect and mechanism of fungal metabolites on CFTR-mediated Cl- secretion. Anti-diarrheal efficacy and the effect of compound on fluid absorption were investigated in mouse closed-loop models. We found that the screening identified arthropsolide A, a fungal metabolite from an endophytic fungus Roussoella sp. PSU-H51, as an inhibitor of CFTR-mediated Cl- secretion in T84 cells (IC50 ~0.8 µM). Arthropsolide A inhibited both CFTR and cAMP-activated basolateral K+ channels. Arthropsolide A had no effect on Na+-K+ ATPase activity. Interestingly, the inhibitory effect of arthropsolide A on CFTR was attenuated by cell depolarization and AMPK inhibition independent of multi-drug resistance protein 4, phosphodiesterases, and protein phosphatases. Importantly, arthropsolide A suppressed cholera toxin (CT)-induced Cl- secretion in T84 cells and CT-induced intestinal fluid secretion in mice by ~75% without affecting intestinal fluid absorption. Taken together, arthropsolide A represents a novel class of fungal metabolites that acts as a potent CFTR inhibitor. Further development of this class of compounds may provide a therapy for secretory diarrheas.

Concise synthesis of α-substituted 2-benzofuranmethamines and other 2-subsituted benzofurans via α-substituted 2-benzofuranmethyl carbocation intermediates.

Propargyl amines 4, where R(3) is aryl, undergo 5-exo-dig cyclization reactions under relatively mild conditions (AgNO(3), DMF, 60 °C, 1 h) to give 3-amino-2,3-dihydro-2-arylmethylidenebenzofurans 5 (R(3) = aryl). In contrast, substrates where R(3) is alkyl undergo competing 6-endo-dig and 5-exo-dig cyclization processes. The hydroxymethyl substrate 4 (R(3) = CH(2)OH), however, was smoothly converted to its corresponding 5-exo-dig cyclization product 5, likely due to the assistance of the primary hydroxyl group in the 5-exo-dig cyclization process by silver cation coordination. Under more enforcing conditions (AgNO(3), DMF, 100 °C, 18 h), the initially formed products 5 undergo a 1,3-allylic rearrangement to their corresponding 2-substituted benzofuran derivatives 6. This rearrangement can also be effected by treating 5 with AgNO(3) in DMF at 100 °C for 18 h or BF(3)·Et(2)O at rt. 2-(3-Butenyl)benzofurans 7 (Nu = allyl) can be prepared by treatment of 5 with BF(3)·Et(2)O and allyltributylstannane. Furan and MeOH could also be employed as external nucleophiles in these BF(3)·Et(2)O-promoted reactions.

A cyclohexenone derivative from Diaporthaceous fungus PSU-H2.

One new cyclohexenone derivative (1) was isolated from Diaporthaceous fungus PSU-H2 together with six known compounds, dothiorelone A (2), dothiorelone C (3), 2,3-dihydromycoepoxydiene (4), (+)-mycoepoxydiene (5), deacetylmycoepoxydiene (6) and tyrosol (7). The structures were elucidated by spectroscopic methods. Their cytotoxic activity against human breast cancer cell line, MCF-7, was evaluated.

Hydronaphthalenones and a dihydroramulosin from the endophytic fungus PSU-N24.

Three new hydronaphthalenone derivatives (1-3) and one new dihydroramulosin derivative (4), were isolated from the endophytic fungus PSU-N24 together with eight known compounds. Their structures were elucidated by spectroscopic methods. Griseofulvin (9) displayed strong antifungal activity against Microsporum gypseum SH-MU-4 with a minimum inhibitory concentration (MIC) value of 2 microg/ml while all metabolites exhibited very weak antibacterial activity (MIC value>or=128 microg/ml) against Staphylococcus aureus, both standard and methicillin-resistant strains. 3-(2-Hydroxypropyl)benzene-1,2-diol (10) showed moderate antimalarial activity against Plasmodiun falciparum with an IC(50) value of 6.68 microg/ml. For antimycobacterial activity against Mycobacterium tuberculosis, compound 3 gave the best activity with the MIC value of 12.50 microg/ml.

Metabolites from the endophytic fungus Phomopsis sp. PSU-D15.

From the endophytic fungus Phomopsis sp. PSU-D15, three metabolites named as phomoenamide (1), phomonitroester (2) and deacetylphomoxanthone B (3), were isolated together with three known compounds, dicerandrol A (4), (1S,2S,4S)-p-menthane-1,2,4-triol (5) and uridine. Their structures were elucidated by spectroscopic methods. Phomoenamide (1) exhibited moderate in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Ra.

Metabolites from the xylariaceous fungus PSU-A80.

One hypoxylonol, xylarenol (1), one hexadienoic acid, xylarenoic acid (2), and one tetralone, xylarenone (3), were isolated from the xylariaceous fungus PSU-A80 together with ten known compounds. The structures were established by analysis of spectroscopic data. 8-Methoxy-1-naphthol, one of the known metabolites, displayed good radical scavenging potency with an IC(50) value of 30 microg/ml.