Two new polycyclic prenylated xanthones (1 and 2) and a new phenylpropanoid glycoside (3), along with seven known compounds (4–10) were isolated from the fruits of Garcinia xanthochymus. The structures were elucidated by 1D- and 2D-NMR, and HRMS experiments. The isolates were evaluated for their inhibitory effects against the viability of U251MG glioblastoma and MDA-MB-231 breast cancer cells that harbor an aberrantly active signal transducer and exhibit activation of transcription 3 (STAT3), and compared to normal NIH3T3 mouse fibroblasts. Among the isolates, compounds 1, 2, 5, and 6–9 inhibited the viability of glioma cancer cells with IC50 values in the range of 1.6–6.5 μM. Furthermore, treatment of U251MG with 6 and 7 inhibited intracellular STAT3 tyrosine phosphorylation and glioma cell migration in vitro, respectively.Download high-res image (116KB)Download full-size image

A new fatty acid ester disaccharide, 2-O-(β-d-glucopyranosyl)-1-O-(2E,4Z,7Z)-deca-2,4,7-trienoyl-β-d-glucopyranose (1), a new ascorbic acid derivative, 2-caffeoyl-3-ketohexulofuranosonic acid γ-lactone (2), and a new iridoid glycoside, 10-dimethoxyfermiloside (3), were isolated along with 13 known compounds (4–16) from fermented noni fruit juice (Morinda citrifolia). The structures of the new compounds, together with 4 and 5, were determined by 1D and 2D NMR experiments, as well as comparison with published values. Compounds 2 and 7 showed moderate inhibitory activities in a TNF-α-induced NF-κB assay, and compounds 4 and 6 exhibited considerable quinone reductase-1 (QR1) inducing effects.

Three new withanolides, physaperuvin G (1), with physaperuvins I (2), and J (3), along with seven known derivatives (4–10), were isolated from the aerial parts of Physalis peruviana. The structures of 1–3 were determined by NMR, X-ray diffraction, and mass spectrometry. Compounds 1–10 were evaluated in lipopolysaccharide (LPS)-activated murine macrophage RAW 264.7 cells. Compounds 4, 5, and 10 with potent nitric oxide inhibitory activity in LPS-activated RAW 264.7 cells, with IC50 values in the range of 0.32–7.8 μM. In addition, all compounds were evaluated for potential to inhibit tumor necrosis factor-alpha (TNF-α)-activated nuclear factor-kappa B (NF-κB) activity with transfected human embryonic kidney cells 293. Compounds 4–7 inhibited TNF-α-induced NF-κB activity with IC50 values in the range of 0.04–5.6 μM.

Chemical investigation of an endophytic fungus Chaetomium globosum isolated from leaves of Wikstroemia uva-ursi led to the isolation of two new azaphilones, chaetoviridins J and K (1 and 3), along with five known derivatives (2 and 4–7). The structures of azaphilones were determined by NMR, X-ray diffraction, Mosher’s method, and CD analysis. The isolated compounds were evaluated for their cancer chemopreventive-potential based on their abilities to inhibit tumor necrosis factor alpha (TNF-α)-induced nuclear factor-kappa B (NF-κB). Compounds 4, 5, 7, and synthetic 8 and 9 inhibit nitric oxide (NO) production with IC50 values in the range of 0.3–5.8 μM. Compounds 4, 5, and 9 also displayed (TNF-α)-induced NF-κB activity with IC50 values in the range of 0.9–5.1 μM.

Four new undecose nucleosides (herbicidin congeners), three known herbicidins, and 9-(β-d-arabinofuranosyl)hypoxanthine (Ara-H) were isolated from the organic extract of a fermentation culture of Streptomyces sp. L-9-10 using proton NMR-guided fractionation. Their structures were elucidated on the basis of comprehensive 1D and 2D NMR and mass spectrometry analyses. These structures included 2′-O-demethylherbicidin F (1), 9′-deoxy-8′,8′-dihydroxyherbicidin B (2), 9′-deoxy-8′-oxoherbicidin B (2a), and the 8′-epimer of herbicidin B (3). This is the first detailed assignment of proton and carbon chemical shifts for herbicidins A, B, and F. The isolated compounds were evaluated for cancer chemopreventive potential based on inhibition of tumor necrosis factor alpha (TNF-α)-induced nuclear factor-kappa B (NF-κB) activity.

Bioassay-guided fractionation of the hexane extract from the flowers of Vernonia cinerea (Asteraceae) led to the isolation of a new sesquiterpene lactone, 8α-hydroxyhirsutinolide (2), and a new naturally occurring derivative, 8α-hydroxyl-1-O-methylhirsutinolide (3), along with seven known compounds (1 and 4–9). The structures of the new compounds were determined by 1D and 2D NMR experiments and by comparison with the structure of compound 1, whose relative stereochemistry was determined by X-ray analysis. The isolated compounds were evaluated for their cancer chemopreventive potential based on their ability to inhibit nitric oxide (NO) production and tumor necrosis factor alpha (TNF-α)-induced NF-κB activity. Compounds 1, 2, 4, 5, and 9 inhibited TNF-α-induced NF-κB activity with IC50 values of 3.1, 1.9, 0.6, 5.2, and 1.6 μM, respectively; compounds 4 and 6–9 exhibited significant NO inhibitory activity with IC50 values of 2.0, 1.5, 1.2, 2.7, and 2.4 μM, respectively.

Bioassay-directed fractionation of the butanol extract of Streptomyces sp. L-4-4, using the hyphae formation inhibition assay of a prokaryotic whole cell, led to the isolation of six new aminocoumarins, coumabiocins A−F (1−6), along with two known compounds, novobiocin (7) and isonovobiocin (8). Coumabiocins A−E (1−5) contain three structural elements, a central 3-amino-7-hydroxycoumarin that is linked at the 3-amino group to a prenylated 4-hydroxybenzoic acid moiety and at the 7-position to an l-noviosyl sugar, while coumabiocin F (6) lacks the sugar moiety. Their structures were elucidated by spectroscopic methods including 1D- and 2D-NMR techniques and mass spectrometric analyses. Coumabiocins A−E (1−5) exhibited significant inhibitory activity against Streptomyces 85E and gave a 10−15 mm clear zone of inhibition at 20 μg/disk and a 10 mm bald and a 10 mm clear zone of inhibition at 5 and 10 μg/disk, respectively, whereas coumabiocin F (6) was inactive.

Bioassay-guided isolation and purification of the ethyl acetate extract of Moringa oleifera fruits yielded three new phenolic glycosides; 4-[(2′-O-acetyl-α-l-rhamnosyloxy) benzyl]isothiocyanate (1), 4-[(3′-O-acetyl-α-l-rhamnosyloxy)benzyl]isothiocyanate (2), and S-methyl-N-{4-[(α-l-rhamnosyloxy)benzyl]}thiocarbamate (3), together with five known phenolic glycosides (4–8). The structures of the new metabolites were determined on the basis of spectroscopic analyses including 1D- and 2D-NMR and mass spectrometry. The anti-inflammatory activity of isolated compounds was investigated with the lipopolysaccharide (LPS)-induced murine macrophage RAW 264.7 cell line. It was found that 4-[(2′-O-acetyl-α-l-rhamnosyloxy)benzyl]isothiocyanate (1) possessed potent NO–inhibitory activity with an IC50 value of 1.67 μM, followed by 2 (IC50 = 2.66 μM), 4 (IC50 = 2.71 μM), and 5 (IC50 = 14.4 μM), respectively. Western blots demonstrated these compounds reduced LPS-mediated iNOS expression. In the concentration range of the IC50 values, no significant cytotoxicity was noted. Structure–activity relationships following NO-release indicated: (1) the isothiocyanate group was essential for activity, (2) acetylation of the isothiocyanate derivatives at C-2′ or at C-3′ of rhamnose led to higher activity, (3) un-acetylated isothiocyanate derivatives displayed eight times less activity than the acetylated derivatives, and (4) acetylation of the thiocarbamate derivatives enhanced activity. These data indicate compounds 1, 2, 4 and 5 are responsible for the reported NO-inhibitory effect of Moringa oleifera fruits, and further studies are warranted.Bioassay-guided isolation and purification of the ethyl acetate extract of Moringa oleifera fruits yielded three new phenolic glycosides; 4-[(2′-O-acetyl-α-l-rhamnosyloxy)benzyl]isothiocyanate (1), 4-[(3′-O-acetyl-α-l-rhamnosyloxy)benzyl]isothiocyanate (2), and S-methyl-N-{4-[(α-l-rhamnosyloxy)benzyl]}thiocarbamate (3). The anti-inflammatory activity of isolated compounds were investigated on lipopolysaccharide (LPS)-induced murine macrophage in RAW 264.7 cell line.

Two new sulfated sesterterpene alkaloids, 19-oxofasciospongine A (3) and fasciospongine C (4), and a new sesterterpene sulfate, 25-hydroxyhalisulfate 9 (5), along with two known sesterterpene sulfates, halisulfates 7 (6) and 9 (7), were isolated from an organic extract of the marine sponge Fasciospongia sp. The structures of the new compounds were established on the basis of one- and two-dimensional NMR spectroscopic studies as well as by HRESIMS analysis. Compounds 1−7 exhibited inhibitory activity against Streptomyces 85E in the hyphae-formation inhibition assay. Compounds 1, 2, and 4−7 were not cytotoxic when tested at 20 μg/mL with MCF-7, LNCaP, and LU cell lines. Only compound 3 demonstrated a moderate cytotoxic effect on the MCF-7 (IC50 13.4 μM), LNCaP (IC50 21.8 μM), and LU-1 cells (IC50 5.0 μM), respectively.

Investigation of a microbial fermentation organic extract of Streptomyces sp. H7667 led to the isolation of three new imides, 3-[(5E)-5-methyl-4-oxo-2-hydroxy-5-octenyl]glutarimide (1), 2-amino-N-2′-(phenylacetyl)propanimide (5), and 2-amino-N-(2′-(cyclohex-2′′-enyl)acetyl)acetimide (6), and one new isoflavonoid glycoside, 6-O-methyl-7-O-α-rhamnopyranosyldaidzein (7), along with four known compounds. Their structures were elucidated by HRESIMS, 1H and 13C NMR, COSY, HMQC, HMBC, and NOESY spectra. Compounds 1−8 were evaluated for their inhibitory activities in the yeast glycogen synthase kinase-3β assay.

A new polybrominated diphenyl ether (9), together with eight known compounds, were isolated from the crude organic extract of the marine sponge Dysidea sp. collected from the Federated States of Micronesia. Their structures were elucidated on the basis of various NMR spectroscopic data. These compounds exhibited inhibitory activities against Streptomyces 85E in the hyphae formation inhibition (HFI) assay and displayed antiproliferative activities against the human breast adenocarcinoma cancer cell line MCF-7. Compound 6 was selected for further evaluation in a cell cycle progression study.

Bioassay-guided fractionation of the dichloromethane extract from the apical bud of Gardenia sootepenesis Hutch. (Rubiaceae) led to the isolation of four new cycloartane triterpenes, sootepins F–I (1–4), along with four known derivatives (5–8). The structures of the new compounds were determined by 1D and 2D NMR experiments and by comparison of the physicochemical data with published values. The isolates were evaluated for cancer chemopreventive potential based on their ability to inhibit nitric oxide (NO) production and tumor necrosis factor-alpha (TNF-α)-induced nuclear factor kappa (NF-κB) activity. Compounds 6–8 inhibited TNF-α-induced NF-κB activity with half maximal inhibitory concentration (IC50) values of 8.3, 5.6, and 6.0 μM, respectively; compounds 7 and 8 showed significant NO-inhibitory activity with IC50 values of 3.2 and 2.0 μM, respectively.Download high-res image (304KB)Download full-size image

Ethnopharmacological relevanceThe two plants investigated here (Fagonia cretica L. and Hedera nepalensis K. Koch) have been previously reported as natural folk medicines for the treatment of diabetes but until now no scientific investigation of potential anti-diabetic effects has been reported.Materials and methodsIn vitro inhibitory effect of the two tested plants and their five isolated compounds on the dipeptidyl peptidase 4 (DPP-4) was studied for the assessment of anti-diabetic activity.ResultsA crude extract of Fagonia cretica possessed good inhibitory activity (IC50 value: 38.1 μg/ml) which was also present in its n-hexane (FCN), ethyl acetate (FCE) or aqueous (FCA) fractions. A crude extract of Hedera nepalensis (HNC) possessed even higher inhibitory activity (IC50 value: 17.2 μg/ml) and this activity was largely retained when further fractionated in either ethyl acetate (HNE; IC50: 34.4 μg/ml) or n-hexane (HNN; 34.2 μg/ml). Bioactivity guided isolation led to the identification of four known compounds (isolated for the first time) from Fagonia cretica: quinovic acid (1), quinovic acid-3β-O-β-d-glycopyranoside (2), quinovic acid-3β-O-β-d-glucopyranosyl-(28→1)-β-d-glucopyranosyl ester (3), and stigmasterol (4) all of which inhibited DPP-4 activity (IC50: 30.7, 57.9, 23.5 and >100 µM, respectively). The fifth DPP-4 inhibitor, the triterpenoid lupeol (5) was identified in Hedera nepalensis (IC50: 31.6 μM).ConclusionThe experimental study revealed that Fagonia cretica and Hedera nepalensis contain compounds with significant DPP-4 inhibitory activity which should be further investigated for their anti-diabetic potential.Download high-res image (222KB)Download full-size image

Bioassay-directed isolation and purification of the crude extract of Withania coagulans, using two assays for cancer chemopreventive mechanisms, led to the isolation of three new steroidal lactones, withacoagulin G (1), withacoagulin H (2), and withacoagulin I (3), along with six known derivatives (4–9). The structures and absolute stereochemistry of these compounds were determined on the basis of spectroscopic analyses, including 1D and 2D NMR, mass spectrometry, and CD analyses. The structure of 1 was confirmed using X-ray diffraction methods. Compounds 1–9 inhibited nitric oxide production in lipopolysaccharide-activated murine macrophage RAW 264.7 cells with IC50 values in the range of 1.9–38.2 μM. Compounds 1 and 2 were the most active (IC50 3.1 and 1.9 μM, respectively). Withanolides 1–9 exhibited inhibition of tumor necrosis factor-α (TNF-α)-induced nuclear factor-kappa B (NF-κB) activation with IC50 values in the range of 1.60–12.4 μM.