Polyketides from the marine-derived fungus Aspergillus falconensis: In silico and in vitro cytotoxicity studies.

Fermentation of the marine-derived fungus Aspergillus falconensis, isolated from sediment collected from the Red Sea, Egypt on solid rice medium containing 3.5% NaCl yielded a new dibenzoxepin derivative (1) and a new natural isocoumarin (2) along with six known compounds (3-8). Changes in the metabolic profile of the fungus were induced by replacing NaCl with 3.5% (NH4)2SO4 that resulted in the accumulation of three further known compounds (9-11), which were not detected when the fungus was cultivated in the presence of NaCl. The structures of the new compounds were elucidated by HRESIMS and 1D/2D NMR as well as by comparison with the literature. Molecular docking was conducted for all isolated compounds on crucial enzymes involved in the formation, progression and metastasis of cancer which included human cyclin-dependent kinase 2 (CDK-2), human DNA topoisomerase II (TOP-2) and matrix metalloproteinase 13 (MMP-13). Diorcinol (7), sulochrin (9) and monochlorosulochrin (10) displayed notable stability within the active pocket of CDK-2 with free binding energy (ΔG) equals to -25.72, -25.03 and -25.37 Kcal/mol, respectively whereas sulochrin (9) exerted the highest fitting score within MMP-13 active center (ΔG = -33.83 Kcal/mol). In vitro cytotoxic assessment using MTT assay showed that sulochrin (9) exhibited cytotoxic activity versus L5178Y mouse lymphoma cells with an IC50 value of 5.1 µM and inhibition of migration of MDA-MB 231 breast cancer cells at a concentration of 70 µM.

The Birch Bracket Medicinal Mushroom, Fomitopsis betulina (Agaricomycetes) - Bioactive Source for Beta-Glucan Fraction with Tumor Cell Migration Blocking Ability.

Wild-grown fruiting bodies of the basidiomycete Fomitopsis betulina (Agaricomycetes, birch bracket mushroom, = Piptoporus betulinus) in different growing stages were collected and analyzed for their beta-glucan content. It could be shown that no significant difference in beta-glucan content regarding size or location of the collected fruiting bodies could be determined, but all samples displayed high values of beta-glucan in comparison to other well-known culinary or medicinal mushroom species. Furthermore, F. betulina fruiting bodies extracted with cold sodium chloride were separated into several fractions by cross flow ultrafiltration, and glucan and protein content were analyzed. The fractions showed varying amounts of beta-glucan and very low protein contents were detected. Also, bioactivity of the fractionated extract was analyzed. None of the mushroom extract fractions induced significant cytotoxicity after 48 h of incubation at a concentration up to 1 mg/mL. Interestingly, in a scratch wound assay, the extract FbS 1, an ultrafiltrated fraction > 300 kDa, was able to block tumor cell migration by 38% compared to solvent control after 48 h of incubation at a concentration of 0.33 mg/mL. In conclusion, our results have high potential for identifying novel antitumor activities based on F. betulina.

Azaphilone pigments and macrodiolides from the coprophilous fungus Coniella fragariae.

Two azaphilone pigments (1 and 2), two dihydrobenzofurans (3 and 4), two macrodiolides (5 and 6), and a dimeric alkyl aromatic constituent (7) were isolated from the goose dung-derived fungus Coniella fragariae. Compounds 1-3 proved to be new natural products. Coniellins H and I (1 and 2) feature a tetracyclic core and an aldehyde group at C-5, which is unusual for azaphilone derivatives. The X-ray structure of pyrenophorin (5) is reported for the first time. Pyrenophorin (5) showed strong cytotoxicity against several cancer cell lines with IC50 values ranging from 0.07 to 7.8 µM.

Selective inhibition of P-gp transporter by goniothalamin derivatives sensitizes resistant cancer cells to chemotherapy.

Overexpression of efflux transporters of the ATP-binding cassette (ABC) transporter family, primarily P-glycoprotein (P-gp), is a frequent cause of multidrug resistance in cancer and leads to failure of current chemotherapies. Thus, identification of selective P-gp inhibitors might provide a basis for the development of novel anticancer drug candidates. The natural product goniothalamin and 21 derivatives were characterized regarding their ability to inhibit ABC transporter function. Among the goniothalamins, selective inhibitors of P-gp were discovered. The two most potent inhibitors (R)-3 and (S)-3 displayed the ability to increase intracellular accumulation of doxorubicin, thereby sensitizing P-gp-overexpressing tumor cells to chemotherapy by decreasing doxorubicin IC50 value up to 15-fold. Molecular docking studies indicated these compounds to inhibit P-gp by acting as transporter substrates. In conclusion, our findings revealed a novel role of goniothalamin derivatives in reversing P-gp-mediated chemotherapy resistance.

Cross-Flow Ultrafiltration Fractions of a Cold Aqueous Extract of the Shiitake Culinary-Medicinal Mushroom, Lentinus edodes (Agaricomycetes), Exhibit Apoptosis in Tumor Cells.

Lentinus edodes (shiitake) ranks among the most well-known medicinal mushrooms worldwide. Immune-modulating effects of shiitake extracts have been widely demonstrated in animals and humans. Apart from providing highly purified compounds such as lentinan, crude mushroom extracts also show antitumor activities. The direct cytotoxicity of crude preparations still requires investigation. The focus of our study lies in the molecular weight cutoff distribution of ß-glucans and proteins in a cold aqueous extract from L. edodes. We applied cross-flow ultrafiltration to obtain 6 fractions with different molecular sizes. ß-glucan and protein contents were quantified. We were able to show that only small amounts of ß-glucans were extracted and that protein content decreases with fraction size. The cytotoxic potential of the cold aqueous preparation was demonstrated by analyzing inhibition of the growth of non-small cell lung cancer and triple-negative breast cancer cells.

Characterization of Cross-Flow Ultrafiltration Fractions from Maitake Medicinal Mushroom, Grifoia frondosa (Agaricomycetes), Reveals Distinct Cytotoxicity in Tumor Cells.

ß-glucans from Basidiomycetes like Grifola frondosa (the maitake mushroom) are well known for their health benefits. Polysaccharide preparations from medicinal mushrooms such as G. frondosa have been successfully tested in a vast number of studies. Many mushroom extracts have been developed and today are merchandized for use medicinally and commercially. Studies could show that, in particular, chemical structural features such as the molecular size of ß-glucans significantly influence their bioactivity. Thus it is highly important to explore the composition and structural properties of ß-glucans extracted from medicinal mushrooms and their effects on human tumor cell viability. Our study focuses on the molecular weight cutoff distribution of ß-glucans in hot water-based extracts from maitake mushrooms. Cross-flow ultrafiltration was applied to obtain 5 fractions of different molecular size. ß-glucan content was quantified using an enzyme-based test kit, specialized to 1,3-1,6-ß-glucans. Here we show that only small amounts of ß-glucans with a high molecular weight (>100 kDa) could be detected from an aqueous extract of G. frondosa. The main compounds encompass substances with a low molecular weight (<5 kDa), composing about 35% of the whole extract. In addition, tumor cell viability studies demonstrate significant cytotoxic potential in 2 different solid cancer cell types for the fraction with a high molecular weight (>100 kDa) and for 1 fraction with a low molecular weight (5-10 kDa). In summary, our experiments prove that cross-flow ultrafiltration serves as a quick and easy method for dividing crude aqueous mushroom extracts into different molecular-weight fractions that inhibit tumor cell viability in vitro.