Extreme effects of Seabuckthorn extracts on influenza viruses and human cancer cells and correlation between flavonol glycosides and biological activities of extracts.

Seabuckthorn is a medicinal plant that is used to prevent cold. It was tested for its metabolic content followed by activity against cancer and virus. The metabolic distribution of different polarity solvent extractions from the leaves was analyzed by LC-MS/MS. Flavonol glycoside contents in EA and Bu extracts were higher than MeOH and DW was observed. MeOH and EA extracts recorded high activity against influenza A/PR virus with IC50 of 7.2 µg/mL and 10.3 µg/mL compared with known drug Oseltamivir of 60.3 µg/mL. A similar trend showed in influenza A/Victoria virus. In case of influenza B viruses such as B/Lee and B/Maryland, EA extract (2.87 µg/mL and 4.5 µg/mL of IC50) emerged strongest among other extracts and Oseltamivir (103.73 µg/mL and 71.6 µg/mL). Each extract showed potent anticancer activities. Interestingly, Bu extract showed stronger anticancer activity against human cancer cells such as NCL-H1299, HeLa, SKOV and Caski (8.2 µg/mL, 8.6 µg/mL, 18.2 µg/mL and 9.2 µg/mL of IC50) respectively. Correlation study reveals that aglycones and flavonol mono-glycosides highly correlated with anti-influenza activities but not correlated with anticancer activities. Reversely, di-glycosides and tri-glycosides have a high correlation with cytotoxic effect with both normal and cancer cells. Therefore, this study provides significant information concerning Seabuckthorn for further medicinal drug development.

Diacetoxyscirpenol as a new anticancer agent to target hypoxia-inducible factor 1.

Hypoxia activates hypoxia-inducible factor 1, which promotes the progression of malignancy by stimulating angiogenesis and by augmenting the ability of tumors to survive. Thus, HIF-1 is one of the most compelling targets for treating cancers. The aim of this study was to find a small molecule that inhibits HIF-1 under hypoxia in cancer cells. 7,280 compounds in a chemical library were tested in a cancer cell line expressing luciferase HIF-dependently. Through three rounds of screening, we finally picked up a compound that originates from a marine bacterium parasitizing red alga. The antibiotic potently inhibited HIF-1 expression and its transcriptional activity in cancer cells exposed to hypoxia. Through two-step fractionation, diacetoxyscirpenol was purified and identified as a HIF-inhibiting ingredient. Mechanistically, diacetoxyscirpenol inhibits the synthesis of HIF-1α protein and also interferes with the dimerization of HIF-1α and ARNT. It attenuates HIF-mediated gene expression in cancer cells exposed to hypoxia, and by doing so reduces tumorigenic and angiogenic potentials of cancer cells. More importantly, diacetoxyscirpenol retarded tumor growth in mice, and reduced HIF-1α expression and vascular formation in the tumors. Overall, diacetoxyscirpenol is considered a potential drug deregulating the HIF-1 signaling pathway, and it could be beneficially employed for treating malignant tumors with hypoxic microenvironment.

Induced production of 6,9-dibromoflavasperone, a new radical scavenging naphthopyranone in the marine-mudflat-derived fungus Aspergillus niger.

The addition of metal bromides (NaBr and CaBr2) during fermentation of the marine-mudflat-derived fungus Aspergillus niger induced production of a new radical scavenging brominated naphthopyranone, 6,9-dibromoflavasperone (1); and three known naphtho-γ-pyranone monomers, flavasperone (2), TMC-256A1 (3), and fonsecin (4); and one naphtho-γ-pyranone dimer, aurasperone B (5). The structure of 6,9-dibromoflavasperone (1) was assigned through the combination of spectroscopic data analyses and comparison with the spectral data of flavasperone (2). Compounds 1-5 displayed potent radical scavenging activity against 2,2-diphenyl-1-picrylhydrazyl, with IC50 values of 21, 25, 0.3, 0.02, and 0.01 µM, respectively, and 3-5 were more potent than the positive control, ascorbic acid (IC50, 20.0 µM).

Cristazine, a New Cytotoxic Dioxopiperazine Alkaloid from the Mudflat-Sediment-Derived Fungus Chaetomium cristatum.

Cristazine (1), a new class of dioxopiperazine alkaloid, along with previously isolated chetomin (2), neoechinulin A (3), and golmaenone (4), were isolated from the mudflat-sediment-derived fungus Chaetomium cristatum. The structure and absolute stereochemistry of 1 was assigned on the basis of NMR, electron impact (EI)-MS, tandem FAB-MS/MS, and circular dichroism (CD) experiments. Compounds 1-4 displayed potent radical-scavenging activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH), with IC50 values of 19, 15, 24, and 20 µM, respectively, which were similar to that of the positive control, ascorbic acid (IC50, 20 µM). Compound 1 also displayed cytotoxic activity against human cervical carcinoma (HeLa) cells, with an IC50 value of 0.5 µM.

The Inhibitory Effect of Alisol A 24-Acetate from Alisma canaliculatum on Osteoclastogenesis.

Osteoporosis is a disease that decreases bone mass. The number of patients with osteoporosis has been increasing, including an increase in patients with bone fractures, which lead to higher medical costs. Osteoporosis treatment is all-important in preventing bone loss. One strategy for osteoporosis treatment is to inhibit osteoclastogenesis. Osteoclasts are bone-resorbing multinucleated cells, and overactive osteoclasts and/or their increased number are observed in bone disorders including osteoporosis and rheumatoid arthritis. Bioactivity-guided fractionations led to the isolation of alisol A 24-acetate from the dried tuber of Alisma canaliculatum. Alisol A 24-acetate inhibited RANKL-mediated osteoclast differentiation by downregulating NFATc1, which plays an essential role in osteoclast differentiation. Furthermore, it inhibited the expression of DC-STAMP and cathepsin K, which are related to cell-cell fusion of osteoclasts and bone resorption, respectively. Therefore, alisol A 24-acetate could be developed as a new structural scaffold for inhibitors of osteoclast differentiation in order to develop new drugs against osteoporosis.

Induced production of methyl bromodihydroxyphenyl acetates by the marine-derived fungus Aspergillus sp.

The addition of metal bromides (NaBr and CaBr2) during fermentation of a marine isolate of the fungus Aspergillus sp. induced production of two new brominated dihydroxyphenylacetic acid derivatives, methyl 2-(6-bromo-3,4-dihydroxyphenyl)acetate (1) and methyl 2-(2,5-dibromo-3,4-dihydroxyphenyl)acetate (2), and a known compound, 2-(3,4-dihydroxyphenyl)acetic acid (3). The structures of the two new compounds (1, 2) were assigned through the combination of spectroscopic data analyses and comparison with the spectral data of compound 3. Compounds 1-3 exhibited potent radical-scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH) with IC50 values (14.2, 12.1, 11.0 µm, respectively) demonstrating greater activity than the positive control (l-ascorbic acid; IC50, 20.0 µm).

New production of 5-bromotoluhydroquinone and 4-O-methyltoluhydroquinone from the marine-derived fungus Dothideomycete sp.

The addition of NaBr to the fermentation medium of a marine isolate of the fungus Dothideomycete sp. resulted in induced production of two toluhydroquinone derivatives, 5- bromotoluhydroquinone (1) and 4-O-methyltoluhydroquinone (2), and two known compounds, toluhydroquinone (3) and gentisyl alcohol (4). The structures of 1 and 2 were assigned through the spectroscopic data analyses. Compounds 1-4 showed a potent antibacterial activity against the methicillinresistant and multidrug-resistant Staphylococcus aureus (MRSA and MDRSA) with MIC (minimum inhibitory concentration) values of 6.2, 12.5, 6.2, and 12.5 microgram/ml, respectively. Compounds 1-4 also exhibited a moderate radical scavenging activity against 1,1-diphenyl-2- picrylhydrazyl (DPPH) with IC(50) values of 11.0, 17.0, 12.0, and 7.0 microM, respectively, which were more active than the positive control, L-ascorbic acid (IC(50), 20.0 µM).

Flavusides A and B, antibacterial cerebrosides from the marine-derived fungus Aspergillus flavus.

Flavusides A (1) and B (2), two new antibacterial cerebroside derivatives, and the previously described phomaligol A (3), kojic acid (4), methyl kojic acid (5), and dimethyl kojic acid (6) have been isolated from the extract of a marine isolate of the fungus Aspergillus flavus. The structure and absolute stereochemistry of two cerebrosides were assigned on the basis of NMR and Tandem FAB-MS/MS experiments. Compounds 1, 2, and 3 exhibited a mild antibacterial activity against Staphylococcus aureus, methicillin-resistant S. aureus, and multidrug-resistant S. aureus. The minimum inhibitory concentration (MIC) values for each strain are as follows: compounds 1 and 2 showed 15.6 µg/ml for S. aureus and 31.2 µg/ml for methicillin-resistant S. aureus and multidrug-resistant S. aureus, and compound 3 exhibited 31.2 µg/ml for S. aureus and methicillin-resistant S. aureus and 62.5 µg/ml for multidrug-resistant S. aureus.