Averantin

Endolichenic fungi are host organisms that live on lichens and produce a wide variety of secondary metabolites. Colorectal cancer stem cells are capable of self-renewal and differentiation into cancer cells, which makes cancers difficult to eradicate. New alternative therapeutics are needed to inhibit the growth of tumor stem cells. This study examined the ability of an extract of Jackrogersella sp. EL001672 (derived from the lichen Cetraria sp.) and the isolated compound 1'-O-methyl-averantin to inhibit development of cancer stemness. The endolichenic fungus Jackrogersella sp. EL001672 (KACC 83021BP), derived from Cetraria sp., was grown in culture medium. The culture broth was extracted with acetone to obtain a crude extract. Column chromatography and reverse-phase HPLC were used to isolate an active compound. The anticancer activity of the extract and the isolated compound was evaluated by qRT-PCR and western blotting, and in cell viability, spheroid formation, and reporter assays. The acetone extract of EL001672 did not affect cell viability. However, 1'-O-methyl-averantin showed cytotoxic effects against cancer cell lines at 50 μg/mL and 25 μg/mL. Both the crude extract and 1'-O-methyl-averantin suppressed spheroid formation in CRC cell lines, and downregulated expression of stemness markers ALDH1, CD44, CD133, Lgr-5, Msi-1, and EphB1. To further characterize the mechanism underlying anti-stemness activity, we examined sonic Hedgehog and Notch signaling. The results showed that the crude extract and the 1'-O-methyl-averantin inhibited Gli1, Gli2, SMO, Bmi-1, Notch-1, Hes-1, and the CSL complex. Consequently, an acetone extract and 1'-O-methyl-averantin isolated from EL001672 suppresses colorectal cancer stemness by regulating the sonic Hedgehog and Notch signaling pathways.

Nine new xanthone-type and anthraquinone-type mycotoxins including austocystins J-N (1-5), 7-chloro versicolorin A (6), 3'-hydroxy-8-O-methyl versicolorin B (7), 8-O-methyl versiconol (8) and 2',3'-dihydroxy versiconol (9), together with 17 known analogues (10-26) were isolated from an extract of the deep-sea-derived fungus Aspergillus puniceus SCSIO z021. Their structures were elucidated by detailed analysis of spectroscopic data, and their absolute configurations were further determined by quantum chemical calculations of ECD spectra or comparison of the experimental ECD spectra. Eleven hydrogenated austocystins were synthesized from 1-2, 10-15 and 17 by catalytic hydrogenation for bioactivities evaluation. Totally, 18 of the all 37 compounds showed strong toxicity against brine shrimps or Vero cell, and the toxicity of 8-O-methyldemethylsterigmatocystin (18) (LC50 = 0.020 µM) against brine shrimps was higher than those of three positive controls. In addition, 22 of the isolated compounds also exhibited significant inhibitory activity against seven different protein tyrosine phosphatases (PTPs), among them austocystin H (15) and methyl-averantin (24) were the most potent inhibitors with IC50 values of 0.20-3.0 µM. Their structure-bioactivity relationship was also discussed.

Ten secondary metabolites, including a new grifolin analog, grifolin B (1); a new homovalencic acid derivative, 12-hydroxyhomovalencic acid (7); and a compound isolated from a natural source for the first time (9), along with seven known compounds, grifolin (2), averantin (3), 7-chloroaverantin (4), 1'-O-methylaverantin (5), 7-hydroxy-2-(2-hydroxypropyl)-5-pentylchromone (6), homovalencic acid (8), and bekeleylactone E (10), were isolated from two fungal strains. The structures of 1-10 were identified by detailed analysis and comparison of their spectroscopic data with literature values. Compounds 9 and 10 showed moderate cytotoxic activity against a panel of cancer cell lines (PC-3, HCT-15, MDA-MB-231, ACHN, NCI-H23, NUGC-3), with the GI50 values ranging from 1.1 µM to 3.6 µM, whereas 1 displayed a weak 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity without cytotoxicity against all tested cell lines.