Xuewei Ye

New Capoamycin-Type Antibiotics and Polyene Acids from Marine Streptomyces fradiae PTZ0025

Capoamycin-type antibiotics (2–5) and polyene acids (6, 7) were isolated from marine Streptomyces fradiae strain PTZ0025. Their structures were established by extensive nuclear magnetic resonance (NMR) and high resolution electron spray ionization mass spectroscopy (HRESIMS) analyses and chemical degradation. Compounds 3, 4, 6, 7 were found to be new and named as fradimycins A (3) and B (4), and fradic acids A (6) and B (7). Compounds 3–5 showed in vitro antimicrobial activity against Staphylococcus aureus with a minimal inhibitory concentration (MIC) of 2.0 to 6.0 μg/mL. Interestingly, Compounds 3–5 also significantly inhibited cell growth of colon cancer and glioma with IC50 values ranging from 0.13 to 6.46 μM. Fradimycin B (4), the most active compound, was further determined to arrest cell cycle and induce apoptosis in tumor cells. The results indicated that fradimycin B (4) arrested the cell cycle at the G0/G1 phase and induced apoptosis and necrosis in colon cancer and glioma cells. Taken together, the results demonstrated that the marine natural products 3–5, particularly fradimycin B (4), possessed potent antimicrobial and antitumor activities.

Bioactive Sulfated Saponins from Sea Cucumber Holothuria moebii

The bioactive ingredients of sea cucumber Holothuria moebii were investigated, and four sulfated saponins (1-4) and one desulfated saponin (3B) with an unusual 3,4-epoxy xylose were obtained from this study. Compound 2 is a new triterpenoid saponin and 3B is a new artificial compound. On the basis of the extensive NMR and HRESIMS data, their structures were assigned as 3-O-[β-D-quinovopyranosyl-(1 → 2)-4-sodium sulfato-β-D-xylopyranosyl]-25-acetoxy-22-oxo-9(11)-holostene-3β,12α,17α-triol (2) and 3-O-[β-D-quinovopyranosyl-(1 → 2)-3,4-epoxy-β-xylopyranosyl]-22,25-epoxy-9(11)-holostene-3β,12α,17α-triol (3B). Compounds 1-4 showed activity suppressing the proliferation of four different glioma cells with IC50 values ranging from 0.99 to 8.64 µM. New saponin 2 significantly induced apoptosis in human glioblastoma U87-MG cells and reduced the expression levels of several glioma metabolic enzymes of glycolysis and glutaminolysis. This study reveals for the first time that selectively targeting multiple glioma metabolic regulators of glycolysis and glutaminolysis might be one of the anti-glioma mechanisms of saponin 2.

A new curvularin glycoside and its cytotoxic and antibacterial analogues from marine actinomycete Pseudonocardia sp. HS7

Five curvularin macrolides (1–5) were isolated from the cultured broth of marine actinomycete Pseudonocardia sp. HS7 that was obtained from the cloacal aperture of sea cucumber Holothuria moebii. The structures of these isolates were characterized as (11S,15R)-11-hydroxycurvularin (1), (11R,15R)-11-hydroxycurvularin (2), curvularin-7-O-α-D-glucopyranoside (3), trans-dehydrocurvularin (4) and curvularin (5) based on their NMR and HRESIMS data as well as chemical degradation. Compound 3 is a new macrolide with a rare α-D-glucopyranose substituent. Compounds 1–4, 5a and 5c (the acyl products of 5), suppressed the proliferation of all six tested cancer cell lines and 4 is the most active compound with IC50 values ranging from 0.59 to 3.39 μM. The 11-hydroxycurvularins 1 and 2 also showed antibacterial activity inhibiting the growth of Escherichia coli.

Bioactive Polycyclic Quinones from Marine Streptomyces sp. 182SMLY.

Chemical investigation of the cultures of marine Streptomyces sp. 182SMLY led to the discovery of two new polycyclic anthraquinones, which were elucidated as N-acetyl-N-demethylmayamycin (1) and streptoanthraquinone A (2) based on the extensive spectroscopic analysis including 2D NMR, HRESIMS, and an electronic circular dichroism (ECD) calculation. Both anthraquinones remarkably suppressed the proliferation of four different glioma cell lines with IC50 values in a range from 0.5 to 7.3 μM and induced apoptosis in the glioma cells. The ratios of IC50 for normal human astrocytes to IC50 for glioma cells were 6.4–53 for 1 and >14–31 for 2. N-acetyl-N-demethylmayamycin (1) also inhibited the growth of methicillin-resistant Staphylococcus aureus with MIC 20.0 μM.

Polyoxygenated 24,28-epoxyergosterols inhibiting the proliferation of glioma cells from sea anemone Anthopleura midori

Eleven sterols (1-11) and one carotenoid (12) were isolated and identified from sea anemone Anthopleura midori. Compounds 1-6 are rare polyoxygenated ergosterols with a 24,28-epoxy moiety. The structures of these epoxyergosterols were determined by NMR and HRESIMS analyses as well as their chemical-physical properties. Epoxyergosterols 1 and 2 were found to be new natural products and 3-6 are new compounds. Bioactive assay showed that compounds 1, 2, 3, 5, 7, 8, 11, and 12 inhibited the proliferation of rat glioma C6 and human glioma U251 cells with IC50 in a range of 2.41-80.45 μM. Further investigation suggested that 1 and 3 induced apoptosis in glioma cells and 1 blocked U251 cells at the G0/G1 phase.

Antitumor activity of caffeic acid 3,4-dihydroxyphenethyl ester and its pharmacokinetic and metabolic properties.

Caffeic acid 3,4-dihydroxyphenethyl ester (CADPE), a natural polyphenol from Sarcandra glabra, has potent in vitro anticancer activity through multiple targets. This study investigated its in vivo anticancer efficacy and its pharmacokinetic and metabolic characteristics. CADPE at any of the dosage regimes (ip 2.5 mg/kg at an interval of 7 h, 12 h, or 24 h for eight days) significantly decreased tumor growth in hepatoma H22 and sarcoma S180 tumor-bearing mice. CADPE also significantly inhibited H22-induced acute ascites development. The in vivo anticancer efficacies of CADPE in these tumor models were equivalent to those of 5-fluorouracil (10 mg/kg, ip) and cyclophosphamide (10 mg/kg, ip), and CADPE did not show any toxicity. A high performance liquid chromatography method with the aid of liquid chromatography/mass spectrometry was established and validated for the pharmacokinetic and metabolic studies of CADPE. CADPE was detected in blood and the organs including liver, kidney, heart, spleen, and brain 1 min after tail intravenous administration, indicating that CADPE was able to quickly distribute to these organs. CADPE was quickly hydrolyzed both in mice and in vitro mice plasma, but was much stable in vitro human plasma, suggesting a better bioavailability of CADPE in human than in mice. The major metabolites of CADPE in mice were caffeic acid, hydroxytyrosol, and a CADPE glucuronide. This was the first time to reveal the pharmacokinetic and metabolic characteristics of CADPE. Taken together, CADPE had potent in vivo antitumor activity and was able to rapidly reach the body organs and to be hydrolyzed in blood to anticancer agents of caffeic acid and hydroxytyrosol. This study suggested that CADPE has the potential for the treatment of cancers and is worthy of further study.

New Metabolites and Bioactive Actinomycins from Marine-Derived Streptomyces sp. ZZ338

An extract prepared from the culture of a marine-derived actinomycete Streptomyces sp. ZZ338 was found to have significant antimicrobial and antiproliferative activities. A chemical investigation of this active extract resulted in the isolation of three known bioactive actinomycins (1–3) and two new metabolites (4 and 5). The structures of the isolated compounds were identified as actinomycins D (1), V (2), X0β (3), 2-acetylamino-3-hydroxyl-4-methyl-benzoic acid methyl ester (4), and N-1S-(4-methylaminophenylmethyl)-2-oxo-propyl acetamide (5) based on their nuclear magnetic resonance (NMR) and high resolution electrospray ionization mass spectroscopy (HRESIMS) data as well as their optical rotation. This class of new compound 5 had never before been found from a natural resource. Three known actinomycins showed activities in inhibiting the proliferation of glioma cells and the growth of methicillin-resistant Staphylococcus aureus, Escherichia coli, and Candida albicans and are responsible for the activity of the crude extract. Actinomycin D (1) was also found to downregulate several glioma metabolic enzymes of glycolysis, glutaminolysis, and lipogenesis, suggesting that targeting multiple tumor metabolic regulators might be a new anti-glioma mechanism of actinomycin D. This is the first report of such a possible mechanism for the class of actinomycins.

Fatsioside A, a rare baccharane-type glycoside inhibiting the growth of glioma cells from the fruits of Fatsia japonica.

A novel baccharane-type triterpenoid glycoside named fatsioside A (1), together with ten oleanane glycosides, were isolated from the fruits of Fatsia japonica. The structure of fatsioside A was assigned as 3β,15α,18α-trihydroxy-18,19-secolupane-12,19-dione 3-O-β-D-glucopyranosyl-(1 → 2)-β-D-glucopyranoside by extensive NMR and HRESIMS analyses. F. japonica is the third baccharane glycoside-containing species reported to date in the plant kingdom, while fatsioside A represents the first baccharane glycoside found in the Araliaceae family. Fatsioside A inhibited the growth of rat glioma C6 cells and human glioma U251 cells with IC50 values of 33.48 ± 2.01 µM and 77.58 ± 6.19 µM, respectively. Further investigation indicated that fatsioside A induced apoptosis and necrosis in glioma cells, and arrested the cell cycle at the G0/G1 phase.

Quantitative determination of triterpenoid glycosides in Fatsia japonica Decne. & Planch. using high performance liquid chromatography.

Fatsia japonica Decne. & Planch. is a triterpenoid glycoside-rich herb with anti-inflammatory activity for the treatment of rheumatoid arthritis. A method for quantitative analysis of the complex triterpenoid glycosides in this medicinal plant has not been established so far. In this study, a high performance liquid chromatography (HPLC) method was developed for simultaneous qualification of 11 glycosides in F. japonica. The analysis was performed on an ODS-2 Hypersil column (250mm×4.6mm, 5μm) with a binary gradient mobile phase of water and acetonitrile. The established HPLC method was validated in terms of linearity, sensitivity, stability, precision, accuracy, and recovery. Results showed that this method had good linearity with R(2) at 0.99992-0.99999 in the test range of 0.04-9.00μg/μL. The limit of detection (LOD) and limit of quantification (LOQ) for the standard compounds were 0.013-0.020μg/μL and 0.040-0.060μg/μL. The relative standard deviations (RSDs%) of run variations were 0.83-1.40% for intra-day and 0.84-3.59% for inter-day. The analyzed compounds in the samples were stable for at least 36h, and the spike recoveries of the detected glycosides were 99.67-103.11%. The developed HPLC method was successfully applied for the measurements of the contents of 11 triterpenoid glycoside in different parts of F. japonica. Taken together, the HPLC method newly developed in this study could be used for qualitative and quantitative analysis of the bioactive triterpenoid glycosides in F. japonica and its products.

Bioactive triterpenoid saponins and phenolic compounds against glioma cells

A total of 54 natural origin compounds were evaluated for their activity in inhibiting the proliferation of glioma cells. Results showed that four Aesculus polyhydroxylated triterpenoid saponins (3-6), six Gleditsia triterpenoid saponins (7-12), and five phenolic compounds (43-46, 51) had dose-dependent activity suppressing the proliferation of both C6 and U251 cells. Structure-activity relationship analysis suggested that the acetyl group at C-28 for the Aesculus saponins and the monoterpenic acid moiety for the Gleditsia saponins could be critical for the activity of these active compounds. Aesculioside H (4), gleditsioside A (7), and feuric acid 3,4-dihydroxyphenethyl ester (FADPE, 46) were the three most active compounds from the different types of the active compounds and induced apoptosis and necrosis in glioma cells.