A new triterpene glycoside from the stems of <Emphasis Type="Italic">Lagerstroemia indica</Emphasis>

A bioassay-guided fractionation and chemical investigation of the stems of Lagerstroemia indica resulted in the isolation and identification of a new triterpene glycoside, lagerindiside (1), along with nine known triterpenes (2–10). The structure of this new compound was elucidated on the basis of 1D and 2D nuclear magnetic resonance spectroscopic data analysis as well as chemical method. The cytotoxic activities of the isolates (1–10) were evaluated by determining their inhibitory effects on four human tumor cell lines (A549, SK-OV-3, SK-MEL-2, and HCT15) using a sulforhodamine B bioassay. Compounds 3 and 4 showed potent cytotoxicity on the tumor cell lines with IC₅₀ values ranging from 3.38 to 6.29 μM.     

Sesquiterpenes from fruits of <Emphasis Type="Italic">Torilis japonica</Emphasis> with inhibitory activity on melanin synthesis in B16 cells

Melanin, a dark macromolecular pigment, protects skin from harmful damage. However, abnormal accumulation is responsible for hyperpigmentation disorders. Melanogenesis inhibitors have therefore become important constituents in cosmetic products for depigmentation. Torilis japonica Decandolle (Umbelliferae) is a biennial plant which is distributed in East Asia. Fruits of this plant have been used for the treatment of skin disease and inflammation. In our previous study, torilin, a major sesquiterpene of T. japonica, showed an inhibitory effect on melanin production in α-melanocyte stimulating hormone (α-MSH)-activated B16 melanoma cells. Further extensive chromatographic separation resulted in thirteen compounds. On the basis of spectroscopic analysis, the structures of the compounds isolated were determined to be three new sesquiterpenes, viz. a guaiane-type, epoxytorilinol (1), a eudesmane-type, elematorilone (2) and a cadinane-type, cardinatoriloside (3), together with ten known sesquiterpenes (4–13). Of the compounds isolated, compounds 4–6 and 11–13 inhibited α-MSH-activated melanin production in B16 melanoma cells with IC₅₀ values from 72.9 to 191.0 μM.     

New limonophyllines A-C from the stem of <Emphasis Type="Italic">Atalantia monophylla</Emphasis> and cytotoxicity against cholangiocarcinoma and HepG2 cell lines

Three new limonoids, limonophyllines A-C (1, 4 and 5), along with two known limonoids (2 and 3) and 11 acridone alkaloids (6-16) were isolated from the stems of Atalantia monophylla. All isolates were evaluated against cholangiocarcinoma, KKU-M156, and HepG2 cancer cell lines. Compounds 12, 14 and 16 displayed cytotoxicity against KKU-M156 cell line with IC₅₀ ranging from 3.39 to 4.1 μg/mL while cytotoxicity against HepG2 cell line with IC₅₀ ranging from 1.43 to 8.4 μg/mL. The structures of all isolated compounds were established by spectroscopic methods including 1D and 2D NMR, IR and mass spectrometry.     

Chemical constituents of the roots of <Emphasis Type="Italic">Codonopsis lanceolata</Emphasis>

A new phenylpropanoid (1), a new alkaloid (11), and a new natural polyacetylene (17), together with nine phenolic compounds (2–10), five alkaloids (12–16), three polyacetylenes (18–20), three triterpenoidal saponins (21–23), one phenylethanoid glycoside (24), and three hexyl glycosides (25–27) with previous known structures, were isolated from the roots of Codonopsis lanceolata. All of the isolates 1–27 were evaluated for their inhibitory effects on LPS-induced nitric oxide (NO) production in RAW 264.7 macrophages and cell viability in A2780 human ovarian cancer cells. Among the isolates, lancemasides A and B have a significant inhibitory effect on the production of NO in RAW264.7 cells (IC₅₀ values?<?50 μM). In A2780 cells, lancemaside A exhibited the most potent inhibitory effect on cell viability. This is the first report on the pharmacological activities of lancemaside B (22).     

Degranulation inhibitors from the arils of <Emphasis Type="Italic">Myristica fragrans</Emphasis> in antigen-stimulated rat basophilic leukemia cells

A methanol extract of mace, the aril of Myristica fragrans (Myristicaceae), was found to inhibit the release of β-hexosaminidase, a marker of antigen-IgE-stimulated degranulation in rat basophilic leukemia cells (RBL-2H3, IC₅₀ = 45.7 μg/ml). From the extract, three new 8-O-4′ type neolignans, maceneolignans I–K (1–3), were isolated, and the stereostructures of 1–3 were elucidated based on spectroscopic and chemical evidence. Among the isolates, maceneolignans A (5), D (6), and H (8), (?)-(8R)-?^8′-4-hydroxy-3,3′,5′-trimethoxy-8-O-4′-neolignan (13), (?)-(8R)-?^8′-3,4,5,3′,5′-pentamethoxy-8-O-4′-neolignan (14), (?)-erythro-(7R,8S)-?^8′-7-acetoxy-3,4-methylenedioxy-3′,5′-dimethoxy-8-O-4′-neolignan (17), (+)-licarin A (20), nectandrin B (24), verrucosin (25), and malabaricone C (29) were investigated as possible degranulation inhibitors (IC₅₀ = 20.7–63.7 μM). These inhibitory activities were more potent than those of the antiallergic agents tranilast (282 μM) and ketotifen fumalate (158 μM). Compounds 5, 25, and 29 also inhibited antigen-stimulated tumor necrosis factor-α production (IC₅₀ = 39.5–51.2 μM), an important process in the late phase of type I allergic reactions.     

Triterpenoid saponins from <Emphasis Type="Italic">Clinopodium chinense</Emphasis> (Benth.) O. Kuntze and their biological activity

Four new ursane-type triterpenoid saponins, clinopoursaponins A–D (1–4), six new oleanane-type triterpenoid saponins, clinopodiside VII–XII (5–10), as well as eight known triterpene analogues (11–18), were isolated from the aerial parts of Clinopodium chinense (Benth.) O. Kuntze. The structures of the new compounds were determined based on extensive spectral analyses, including 1D (¹H and ¹³C) and 2D NMR experiments (COSY, NOESY, HSQC, 2D TOCSY, HSQC-TOCSY and HMBC), HR-ESI-MS and chemical methods. Compounds 1–18 were evaluated for their protective effects against anoxia/reoxygenation-induced apoptosis in H9c2 cells and cytotoxicities against murine mammary carcinoma cell line 4T1. Compounds 8, 9 and 18 exhibited significant protective effects, while compound 1 exhibited cytotoxic activity with IC₅₀ value of 7.4 μm compared to 7.6 μm for the positive control 10-hydroxycamptothecin.     

Design,synthesis and biological evaluation of novel thiophene and theinopyrimidine derivatives as anticancer agents

Some novel thiophene and theinopyrimidine derivatives have been synthesized. Their structures were confirmed by elemental analyses, infrared, ¹H NMR, ¹³C NMR and mass spectral data. All the target compounds were screened against liver adenocarcinoma (HepG2) cell line. Compounds 9c, 9b, 10b, and 7c in a sequent were the most potent compounds between all the test compounds with IC₅₀ values [0.01063, 0.01158, 0.01729, 0.01957?µM], respectively. Compounds 13b, 7b, 5d, 9a, 8a, and 11b showed higher activity with IC₅₀ values ranged from 0.02231 to 0.03673?µM when compared with 5-flurouracil (A) as a reference drug (IC₅₀?=?0.0384?µM).     

Versicolols A and B,two new prenylated isocoumarins from endophytic fungus <Emphasis Type="Italic">Aspergillus versicolor</Emphasis> and their cytotoxic activity

Versicolols A and B (1 and 2), two rare prenylated isocoumarin derivatives, along with five known isocoumarins (3–7) were isolated from the fermentation products of an endophytic fungus Aspergillus versicolor. Their structures were elucidated on the basis of extensive spectroscopic analysis, including 1D- and 2D-NMR techniques. Compounds 1 and 2 were evaluated for their cytotoxicity against five human tumor cell lines. The results showed that compounds 1 exhibited weak cytotoxicity against A549 and MCF7 cells with IC₅₀ values of 9.4 and 8.8 μm, and compound 2 exhibited weak cytotoxicity against SHSY5Y and MCF7 cells with IC₅₀ values of 8.2 and 6.8 μm, respectively.     

Constituents of PG201 (Layla<Superscript>®</Superscript>), a multi-component phytopharmaceutical,with inhibitory activity on LPS-induced nitric oxide and prostaglandin E<Subscript>2</Subscript> productions in macrophages

Fourteen compounds, coumarin (1), demethylsuberosin (2), xanthotoxin (3), psoralen (4), decursinol (5), decursin (6), decursinol angelate (7), chikusetsusaponin IVa (8), chikusetsusaponin IVa methyl ester (9), ethyl caffeate (10), syringaresinol (11), cnidilide (12), farnesol (13), and linoleic acid (14), were isolated from phytopharmaceutical PG201 (Layla^®) by activity-guided fractionation utilizing inhibitory activity on nitric oxide (NO) production in vitro. The isolates 1–14 were evaluated for their inhibitory activity on LPS-induced NO and prostaglandin E₂ (PGE₂) productions in RAW 264.7 cells. All the compounds except 14 displayed suppressive effects on LPS-induced NO and PGE₂ production with IC₅₀ values ranging from 8 to 60 μM. Among these, compound 10 showed the most potent inhibitory effect on NO production from RAW 264.7 cells with an IC₅₀ value of 8.25 μM. Compounds 2, 9, and 10 exhibited high inhibitory effects on PGE₂ production with the IC₅₀ values of 9.42, 7.51, and 6.49 μM, respectively. These findings suggest that compounds 2, 9, and 10 are the potential anti-inflammatory active constituents of PG201 and further study may be needed to explain their mechanism of action.     

Cytotoxic constituents of <Emphasis Type="Italic">Oldenlandia umbellata</Emphasis> and isolation of a new symmetrical coumarin dimer

The study was aimed at exploring cytotoxic activity of Oldenlandia umbellata and its chemical constituents. Cell viability assay of crude methanolic extract of aerial parts of O. umbellata (HUM), its ether soluble fraction (HUM-E) and butanol soluble fraction (HUM-B) against colon cancer HT-29, lung epithelial A549 and breast adenocarcinoma MDA-MB-231 cell lines showed HUM-E to be significantly cytotoxic with IC₅₀ values of 25.7, 67.7 and 69.3 μg/mL, against HT-29, A549 and MDA-MB-231, respectively. Chemical investigation of HUM-E and HUM-B resulted in the isolation of a novel symmetrical coumarin dimer named oledicoumarin (1), together with eleven known compounds, hedyotiscone B (2), cedrelopsin (3), pheophorbide A methyl ester (4), deacetyl asperuloside (5), scandoside methyl ester (6), asperulosidic acid (7), scandoside (8), nicotinic acid (9), 6α-hydroxy geniposide (10) anthragallol 1,2-dimethyl ether (11) and anthragallol 1,3-dimethyl ether (12). All compounds were isolated for the first time from O. umbellata except anthragallols. This is the foremost report exploring the presence of coumarin derivatives in O. umbellata. Testing of cytotoxicity of isolated constituents revealed that compounds 3, 4, 11 and 12 showed significant inhibition against A549 cells with IC₅₀ values of 3.6–5.9 μg/mL. Compounds 4, 11 and 12 showed marked inhibitory effect against MDA-MB-231 cells (IC₅₀ 3.6–9.1 μg/mL). Compounds 4 (IC₅₀ 1.7 μg/mL) and 7 (IC₅₀ 6.1 μg/mL) were highly active against HT-29 cells. In summary, the less polar fraction of O. umbellata and its constituents were found to be cytotoxic.     

Induced production of 6,9-dibromoflavasperone,a new radical scavenging naphthopyranone in the marine-mudflat-derived fungus <Emphasis Type="Italic">Aspergillus niger</Emphasis>

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).     

Two new benzylisoquinoline alkaloids from <Emphasis Type="Italic">Thalictrum</Emphasis><Emphasis Type="Italic">foliolosum</Emphasis> and their antioxidant and in vitro antiproliferative properties

Two novel rare chloro-containing benzylisoquinoline alkaloids, thalfoliolosumines A (1) and B (2), along with eight known isoquinoline alkaloids (3–10) were isolated from the whole plant of Thalictrum foliolosum. The structures of these compounds were elucidated by spectral analyses, including 1D and 2D NMR (COSY, HSQC, HMBC and NOESY) experiments. The antiproliferative effects of all the isolated compounds were evaluated by MTT method against MCF-7, PC-3, and U937 cells, and trypan blue method against HL-60 cells. New compounds 1 and 2 exhibited moderate in vitro antiproliferative activity against MCF-7, PC-3, and HL-60 cells, and good inhibitory effects against U937 cells with IC₅₀ values of 7.50 and 6.97 μM, respectively. Compounds 7 and 10 showed the strongest in vitro antiproliferative with IC₅₀ values of 0.93 and 1.69 μM against HL-60 cell line. The antioxidant properties were also measured, bisbenzyltetrahydroisoquinoline alkaloids 3–6 showed the strongest antioxidant activities in ABTS assay.     

Anti-inflammatory and anticholinesterase activity of six flavonoids isolated from <Emphasis Type="Italic">Polygonum</Emphasis> and <Emphasis Type="Italic">Dorstenia</Emphasis> species

This study was aimed at investigating the anti-inflammatory and anticholinesterase activity of six naturally occurring flavonoids: (?) pinostrobin (1), 2′,4′-dihydroxy-3′,6′-dimethoxychalcone (2), 6-8-diprenyleriodictyol (3), isobavachalcone (4), 4-hydroxylonchocarpin (5) and 6-prenylapigenin (6). These compounds were isolated from Dorstenia and Polygonum species used traditionally to treat pain. The anti-inflammatory activity was determined by using the Griess assay and the 15-lipoxygenase inhibitory activity was determined with the ferrous oxidation-xylenol orange assay. Acetylcholinesterase inhibition was determined by the Ellman’s method. At the lowest concentration tested (3.12 µg/ml), compounds 2, 3 and 4 had significant NO inhibitory activity with 90.71, 84.65 and 79.57 % inhibition respectively compared to the positive control quercetin (67.93 %). At this concentration there was no significant cytotoxicity against macrophages with 91.67, 72.86 and 70.86 % cell viability respectively, compared to 73.1 % for quercetin. Compound 4 had the most potent lipoxygenase inhibitory activity (IC₅₀ of 25.92 µg/ml). With the exception of (?) pinostrobin (1), all the flavonoids had selective anticholinesterase activity with IC₅₀ values ranging between 5.93 and 8.76 µg/ml compared to the IC₅₀ 4.94 µg/ml of eserine the positive control. These results indicate that the studied flavonoids especially isobavachalcone are potential anti-inflammatory natural products that may have the potential to be developed as therapeutic agents against inflammatory conditions and even Alzheimer’s disease.     

Phenylpropanoid ester from <Emphasis Type="Italic">Zingiber officinale</Emphasis> and their inhibitory effects on the production of nitric oxide

A new phenylpropanoid ester mixture, (E)-geranylferulic acid (1a) and (Z)-geranylferulic acid (1b), along with 13 known compounds, [6]-gingerol (2), [8]-gingerol (3), [10]-gingerdione (4), 1-dehydro-[6]-gingerdione (5), 1-dehydro-[8]-gingerdione (6), [6]-paradol (7), [8]-paradol (8), [6]-gingeroldiacetate (9), 6-hydroxy-[6]-shogaol (10), galanolactone (11), trans-®-sesquiphellandrol (12), trans-sesquipiperitol (13), and 4α,5β-dihydroxybisabola-2,10-diene (14) were isolated from ethanol extract of Zingiber officinale. Their structures were determined based on the spectroscopic (1D, 2D-NMR and MS) and chemical evidence. All of the isolates were evaluated for their potential to inhibit LPS-induced production of nitric oxide in murine macrophage RAW264.7 cells. Compounds 1–12 were found to inhibit nitric oxide production with IC₅₀ values ranging from 5.5 to 28.5 μM.     

New neo-lignan from <Emphasis Type="Italic">Acanthopanax senticosus</Emphasis> with protein tyrosine phosphatase 1B inhibitory activity

New neo-lignan, (7S, 8R)-3-hydroxyl-4-methoxyl-balanophonin (1), together with seven known compounds (2–8) were isolated from the EtOAc-soluble extract of Acanthopanax senticosus. The structure of the new neo-lignan was elucidated with spectroscopic and physico-chemical analyses. All the isolates were evaluated for in vitro inhibitory activity against PTP1B, VHR and PP1. Among them, the new compound (1) was found to exhibit selective inhibitory activity on PTP1B with IC₅₀ value 15.2 ± 1.4 µM.     

Chemical constituents from <Emphasis Type="Italic">Phyllanthus emblica</Emphasis> and the cytoprotective effects on H<Subscript>2</Subscript>O<Subscript>2</Subscript>-induced PC12 cell injuries

Two new compounds (1–2), including a bisabolane-type sesquiterpenoid (1), one new diphenyl ether derivative (2), together with 23 known compounds (3–25), were isolated from the fruits of Phyllanthus emblica. Their structures were elucidated by detailed spectroscopic analysis. All the isolated compounds were screened for the DPPH scavenging effects and cytoprotective effects against H₂O₂ induced PC12 cells injury. Compounds 12–15 showed significant DPPH scavenging effects with the IC₅₀ values in the range of 3.25–4.18 μM. Among these potential antioxidants, compound 14 improved the survival of PC12 cells after H₂O₂ exposure without showing any cytotoxicity at the tested concentrations.     

Monoterpene esters and aporphine alkaloids from <Emphasis Type="Italic">Illigera aromatica</Emphasis> with inhibitory effects against cholinesterase and NO production in LPS-stimulated RAW264.7 macrophages

Three new monoterpene phenylpropionic acid esters, illigerates A–C (1–3), and one new aporphine alkaloid, illigeranine (4), as well as four known ones, actinodaphnine (5), nordicentrine (6), 8-hydroxy carvacrol (7), and 3-hydroxy-α,4-dimethyl styrene (8), were isolated from the tubers of Illigera aromatica. The structures of 1–4 were identified by HRESIMS, 1D and 2D NMR, and electronic circular dichroism spectra. Compound 1 potently inhibited NO production in LPS-stimulated RAW264.7 cells with an IC₅₀ value of 18.71 ± 0.85 μM; compound 1, 3, and 4 showed moderate butyrylcholinesterase inhibitory activities with the IC₅₀ values of 46.86 ± 0.65, 53.51 ± 0.71, and 31.62 ± 1.15 μM, respectively. Compound 4 showed weak AChE inhibitory activity with an IC₅₀ value of 81.69 ± 2.07 μM, and compounds 5 and 6 possessed moderate AChE inhibitory activities with the IC₅₀ values of 47.74 ± 1.66 and 40.28 ± 2.73 μM, respectively. This paper provides a chemical structure and bioactive foundation for using I. aromatica as an herbal medicine.     

New geranyl flavonoids from the leaves of <Emphasis Type="Italic">Artocarpus communis</Emphasis>

Four new geranyl flavonoids 1–4 and four known flavonoids 5–8 were obtained from the leaves of Artocarpus communis collected in Indonesia. The planar structures of flavonoids were elucidated by analyses of MS and NMR spectroscopic data. Absolute configurations of 1 and 2 were determined by ECD spectroscopy. Analyses by HPLC with a chiral-phase column and ECD spectra confirmed that 3 and 4 were stereoisomeric mixtures and 7 and 8 were racemic mixtures. The compounds obtained in this study inhibited the enzymatic activities of ubiquitin-specific protease 7 (USP7) and the chymotrypsin-like activity of the proteasome. Among the geranyl flavonoids tested in this experiment, the USP7 inhibitory activity of 6 (IC₅₀ value, 0.094 μM) was 55 times more potent than the commercially available positive control, P5091 (IC₅₀ value, 5.2 μM).     

Lignan constituents of Tilia amurensis and their biological evaluation on antitumor and anti-inflammatory activities

In the recent decade, numerous lignan derivatives isolated from plants have been proven to have the potential as an anti-cancer substance. On the search for anti-cancer compounds from Korean medicinal plants, the methanolic extract from the trunk of Tilia amurensis Rupr. (Tiliaceae) was found to have significant cytotoxicity against A549 (lung carcinoma), SK-OV-3 (ovary malignant ascites), SK-MEL-2 (skin melanoma), and HCT-15 (colon adenocarcinoma) in our screening test. Hence, a bioassay-guided fractionation and chemical investigation of the methanolic extract resulted in the isolation and identification of 10 lignan derivatives (1–10) including two new lignan glycosides named tiliamurosides A (1) and B (2). The structures of these new compounds were determined by spectroscopic methods, namely 1D and 2D nuclear magnetic resonance (NMR) techniques, high resolution mass spectrometry (HRMS), circular dichroism (CD) data, and chemical methods. Tiliamuroside B (2) and schizandriside (3) showed significant cytotoxicity against A549, SK-OV-3, SK-MEL-2, and HCT-15 cell lines with inhibitory concentration (IC₅₀) values of 3.26–8.89 μM. Moreover, (−)-syringaresinol (8) and (−)-pinoresinol 4-O-β-d-glucopyranoside (10) significantly inhibited nitric oxide (NO) production in murine microglia BV-2 with IC₅₀ values of 15.05 and 34.35 μM, respectively.     

Identification of <Emphasis Type="Italic">N</Emphasis>-arylsulfonylpyrimidones as anticancer agents

For confirming the role of five membered ring of imidazolidinone moiety of N-arylsulfonylimidazolidinones (7) previously reported with highly potent anticancer agent, a series of N-arylsulfonylpyrimidones (10a–g) and N-arylsulfonyltetrahydropyrimidones (11a–e) were prepared and their anti-proliferating activity was measured against human cancer cell lines (renal ACHN, colon HCT-15, breast MDA-MB-231, lung NCI-H23, stomach NUGC-3, and prostate PC-3) using XTT assay. Among them, 1-(1-acetylindolin-5-ylsulfonyl)-4-phenyltetrahydropyrimidin-2(1H)-one (11d, mean GI₅₀ = 3.50 µM) and ethyl 5-(2-oxo-4-phenyltetrahydropyrimidin-1(2H)-ylsulfonyl)-indoline-1-carboxylate (11e, mean GI₅₀ = 0.26 µM) showed best growth inhibitory activity against human cancer cell lines. Considering the activity results, N-arylsulfonyltetrahydropyrimidones (11) exhibited more potent activity compared to N-arylsulfonylpyrimidones (10) and comparable activity to N-arylsulfonylimidazolidinones (7). Especially, tetrahydropyrimidin-2(1H)-one analogs containing acylindolin-5-ylsulfonyl moiety at position 1 demonstrated their strong growth inhibitory activity against human cancer cell lines.