Isoprenyl phenolic ethers from the termite nest-derived medicinal fungus Xylaria fimbriata.

Seven new isoprenyl phenolic ethers, namely fimbriethers A‒G (1‒7), were isolated from the fermented broth of the termite nest-derived medicinal fungus Xylaria fimbriata YMJ491. Their structures were determined by spectroscopic data analysis and compared with those reported. The effects of all the isolates at a concentration of 100 µM on the inhibition of nitric oxide (NO) production in lipopolysaccharide (LPS)-induced murine macrophage RAW 264.7 cells were evaluated, and all of them exhibited NO production inhibitory activity with Emax values ranging from 4.6 ± 2.0% to 49.7 ± 0.5% without significant cytotoxicity. In addition, these seven compounds did not alter phenylephrine-induced vasocontraction in isolated intact thoracic aortic rings from C57BL/6J mouse, indicating 1‒7 were not involved in the regulation of endothelial NOS-mediated NO production.

Identification of 7-(4'-Cyanophenyl)indoline-1-benzenesulfonamide as a mitotic inhibitor to induce apoptotic cell death and inhibit autophagy in human colorectal cancer cells.

Targeting cellular mitosis in tumor cells is an attractive cancer treatment strategy. Here, we report that B220, a synthetic benzenesulfonamide compound, could represent a new mitotic inhibitor for the treatment of colorectal cancer. We examined the action mechanism of B220 in the colorectal carcinoma HCT116 cell line, and found that treatment of cells with B220 caused cells to accumulate in G2/M phase, with a concomitant induction of the mitotic phase markers, MPM2 and cyclin B1. After 48 h of B220 treatment, cells underwent apoptotic cell death via caspase-3 activation and poly(ADP ribose) polymerase (PARP) cleavage. In addition, B220 inhibits autophagy by blocking conversion of microtubule-associated protein 1 light chain 3 (LC3-I) to LC3-II and inhibiting autophagic flux. Notably, blockade of autophagy by pharmacological inhibition or using an Atg5-targeting shRNA reduced B220-induced cytotoxicity. Conversely, the autophagy inducer NVP-BEZ235 shows a synergistic interaction with B220 in HCT116 cells, indicating autophagy was required for the observed cell death. In summary, these results indicate B220 combined with the induction of autophagy using the dual PI3K/mTOR inhibitor, NVP-BEZ235, might be an attractive strategy for cancer therapy, and provides a framework for further development of B220 as a new therapeutic agent for colon cancer treatment.

Meroterpenoids from a Medicinal Fungus Antrodia cinnamomea.

Antrodia cinnamomea, a medicinal fungus indigenous to Taiwan, has been shown to exhibit a broad spectrum of bioactivities for the treatments of alcoholic intoxication, diarrhea, abdominal pain, and fatigue, and a number of active principles have been identified. Among the bioactive entities, clinical trials of antroquinonol and 4-acetyl antroquinonol B are being carried out for curing cancer, hypercholesterolemia, and hyperlipidemia. The total synthesis of antroquinonol has been achieved; however, investigating the structure-activity relationship of this class of compounds remained difficult due to the lack of available analogues. Twenty antroquinonols isolated from A. cinnamomea IFS006 are reported herein. Their structures were elucidated using spectral analysis and by comparison with literature values. Of these, 11 antroquinonol analogues, namely, antroquinonols N-X (1-11), were previously unreported. The growth inhibitory activity of all the antroquinonol analogues was evaluated against human A549 and PC-3 cancer cell lines, and antroquinonol A exhibited the most potent activity, with GI50 values of 5.7 ± 0.2 and 13.5 ± 0.2 µM, respectively. Antroquinonols V (9) and W (10) also showed growth inhibitory activity against A549 cells with GI50 values of 8.2 ± 0.8 and 7.1 ± 2.1 µM, respectively, compared to 5-fluorouracil (GI50 = 4.2 ± 0.2 µM).

Identification of the orsellinic acid synthase PKS63787 for the biosynthesis of antroquinonols in Antrodia cinnamomea.

Antrodia cinnamomea, an endemic basidiomycete used as a health food in Taiwan, is known to synthesize antroquinonols, which were reported to have notable medicinal potential in oncology and immunology. However, the biosynthetic pathway of these compounds is currently unclear. Our previous study showed that a pks63787 knockout mutant of A. cinnamomea (∆pks63787) is deficient in the biosynthesis of several aromatic metabolites. In this study, we pointed by phylogenetic analysis that pks63787 likely encodes an orsellinic acid synthase. Moreover, amendment of the cultural medium with orsellinic acid not only restores the ability of ∆pks63787 to produce its major pigment and other deficient metabolites, e.g., antroquinonols, but also enhances the productivity of several antroquinonols, including two new compounds 2 and 3. These results provide direct evidence that the PKS63787 is involved in the biosynthesis of antroquinonols and confirmed our hypothesis that the 6-methylcyclohexenone moiety was synthesized via the PKS63787-mediated polyketide pathway. In conclusion, PKS63787 might function as orsellinic acid synthase and orsellinic acid is an important precursor indispensable for the biosynthesis of the major pigment and antroquinonols in A. cinnamomea. To facilitate further basic or applied study, a putative biosynthesis pathway map of antroquinonols is proposed.