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.     

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.     

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.     

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 phenylpropanoids from <Emphasis Type="Italic">Bulbophyllum retusiusculum</Emphasis>

Two new phenylpropanoids, retusiusines A (1) and B (2), and a pair of new phenylpropyl enantiomers, (±)-retusiusine C (3a and 3b), together with eight known compounds, dihydroconiferyl dihydro-p-coumarate (4), methyl 3-(4-hydroxyphenyl) propionate (5), 3-(4-hydroxyphenyl)-propanoic acid (6), dihydroferulic acid (7), methyl 3-(4-methoxyphenyl) propionate (8), 3-(3,4-dimethoxyphenyl)-2-propenal (9), trans-p-coumaric acid (10) and dihydroconiferyl alcohol (11), were isolated from the tubers of Bulbophyllum retusiusculum. The absolute configurations of the new compounds were determined by calculating their electronic circular dichroism (ECD), spectra and specific optical rotations and comparing the calculated values with the experimental data. Compound 2 exhibited potent antifungal activity against Candida albicans (16 μg/mL). Compound 3 showed moderate antibacterial activity against Bacillus subtilis (64 μg/mL).     

Anti-inflammatory activity of compounds from the rhizome of <Emphasis Type="Italic">Cnidium officinale</Emphasis>

Five new compounds, 9,3′-dimethoxyhierochin A (1), 6-oxo-trans-neocnidilide (2), (±)-(3E)-trans-6-hydroxy-7-methoxydihydroligustilide (3), (±)-cnidiumin (4), and 6-(1-oxopentyl)-salicylic acid methyl ester (5), together with twenty known compounds (6–25), were isolated from the rhizome of Cnidium officinale. The chemical structures of new compounds were established by NMR spectroscopic techniques, mass spectrometry, Mosher’s method, and CD spectrum. Their anti-inflammatory activities were evaluated against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in macrophage RAW 264.7 cells. Compounds 7, 13, and 14 showed inhibitory effects with IC₅₀ values of 5.1, 24.5, and 27.8 μM, respectively. In addition, compounds 7, 13, and 14 reduced LPS-induced inducible nitric oxide synthase (iNOS) expression and cyclooxygenase-2 (COX-2) protein in a concentration-dependent manner.     

Soluble epoxide hydrolase inhibitory activity by rhizomes of <Emphasis Type="Italic">Kaempferia parviflora</Emphasis> Wall. ex Baker

In our search for natural soluble epoxide hydrolase (sEH) inhibitors from plants, we found that the methanolic extract of the rhizomes of Kaempferia parviflora Wall. ex Baker (Zingiberaceae) significantly inhibits sEH in vitro. In a phytochemical investigation of dichloromethane fraction of K. parviflora rhizomes, we isolated sixteen compounds (1–16), including flavonoid derivatives (1–12), anthraquinones (13 and 14), triterpene (15), and triterpene glycoside (16). The structures of the isolated compounds were established in an extensive 1D and 2D NMR, as well as MS analysis. The sEH inhibitory activities of all isolated compounds were evaluated. Among the isolated flavonoid derivatives, 4, 6, 8, 10, and 12 were identified as potent inhibitors of sEH, with IC₅₀ values ranging from 0.9 ± 0.1 to 4.5 ± 0.1 μM. In addition, a kinetic analysis of the flavonoid derivatives (1–12) revealed that the inhibitory activity of flavonoid derivatives 1–4 and 6–12 is mixed with K _i values ranging from 0.1 ± 0.0 to 14.3 ± 0.3 μM, whereas compound 8 was a non-competitive with K _i = 0.3 ± 0.0 μM. These findings suggest that flavonoid derivatives from K. parviflora rhizomes are potential novel sEH inhibitors.     

Anti-inflammatory effects of secondary metabolites isolated from the marine-derived fungal strain <Emphasis Type="Italic">Penicillium</Emphasis> sp. SF-5629

After the chemical investigation of the ethyl acetate extract of the marine-derived fungal strain Penicillium sp. SF-5629, the isolation and structural elucidation of eight secondary metabolites, including (3R,4S)-6,8-dihydroxy-3,4,7-trimethylisocoumarin (1), (3S,4S)-sclerotinin A (2), penicitrinone A (3), citrinin H1 (4), emodin (5), ω-hydroxyemodin (6), 8-hydroxy-6-methyl-9-oxo-9H-xanthene-1-carboxylate (7), and 3,8-dihydroxy-6-methyl-9-oxo-9H-xanthene-1-carboxylate (8) were carried out. Evaluation of the anti-inflammatory activity of these metabolites showed that 4 inhibited nitric oxide and prostaglandin E2 production in lipopolysaccharide-stimulated BV2 microglia, with IC₅₀ values of 8.1 ± 1.9 and 8.0 ± 2.8 μM, respectively. The inhibitory function of 4 was confirmed based on decreases in inducible nitric oxide synthesis and cyclooxygenase-2 gene expression. In addition, 4 was found to suppress the phosphorylation of inhibitor kappa B-α, interrupt the nuclear translocation of nuclear factor kappa B, and decrease the activation of p38 mitogen-activated protein kinase.     

New podolactones from the seeds of <Emphasis Type="Italic">Podocarpus nagi</Emphasis> and their anti-inflammatory effect

Podolactones are a class of structural diverse diterpenoid lactones, mainly isolated from the Podocarpus species. Several bioactivities have been disclosed for podolactones, including cytotoxicity and anti-atherosclerosis. In this study, the seeds of P. nagi were isolated by comprehensive chromatographic methods to obtain three new podolatones, named nagilactone B 1-O-β-d-glucoside (1), nagilactone N3 3-O-β-d-glucoside (2), and 2-epinagilactone B (3), as well as a known compound, nagilactone B (4). Their structures were determined by analyses of NMR and HRESIMS data. Compounds 1 and 2 significantly inhibited nitric oxide (NO) production on LPS-stimulated RAW264.7 macrophages, with IC₅₀ values of 0.18?±?0.04 and 0.53?±?0.03 μM, respectively. Indomethacin (IC₅₀ 4.21?±?0.32 μM) was used as a positive control. Compound 1 suppressed the expression of inducible NO synthase (iNOS) in a concentration-dependent manner, mediating through inhibiting nuclear factor-κB (NF-κB) activity. This is the first report regarding the anti-inflammatory effect of podolactones, which could be potential anti-inflammatory agents.     

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).     

Alkyl phenols,alkenyl cyclohexenones and other phytochemical constituents from <Emphasis Type="Italic">Lannea rivae</Emphasis> (chiov) Sacleux (Anacardiaceae) and their bioactivity

Six novel compounds, 3-nonadec-14′-(Z)-enyl phenol (1a); 4,5-dihydroxy-4,2′-epoxy-5-[16′-Z-18′-E-heneicosenyldiene]-cyclohex-2-enone (2), 2,4,5-trihydroxy-2-[16′-Z-heneicosenyl]-cyclohexanone (3); 4S,6R-dihydroxy-6-[12′-Z-heptadecenyl]-cyclohex-2-enone (4a); 4S,6R-dihydroxy-6-[14′-Z-nonadecenyl]-cyclohex-2-enone (4b); and 1,2,4-trihydroxy-4-[16′-Z-heneicosenyl]-cyclohexane (5) were identified from the roots and stems of Lannea rivae in addition to the known cardanols, 3-heptadec-12′-Z-enyl phenol (1b), 3-pentadec-10′-Z-enyl phenol (1c) and 3-pentadecyl phenol (1d), sitosterol (6), sitosterol glucoside (7), taraxerone (8), taraxerol (9), E-lutein (10), myricetin (11), myricetin-3-O-α-rhamnopyranoside (12), myricetin-3-O-β-galactopyranoside (13) and (-)-epicatechin-3-O-gallate (14). The ketones 4a and 4b were isolated as a mixture and were qualitatively separated and identified by GCMS. Myricetin (11) and epicatechin gallate (14) displayed over 90 % DPPH radical-scavenging activity at 50 μg mL^?1, while its glycosides (12 and 13) showed percentages of over 70 % in the same assay. The same compounds 11 and 14 showed antibacterial activity similar to erythromycin and vancomycin against Gram-positive bacteria and were also active against Gram-negative bacteria, but not as much as the cefuroxime, ciprofloxacin and nalidixic acid standards. Compounds 1a–d, 4a–b and 5 were all relatively non-toxic, while 2 (the epoxy cyclohex-2-enone) and 3 (the trihydroxy cyclohexanone) showed more toxicity than the others. These two toxic compounds, 2 and 3 also showed antiplasmodial activity with IC₅₀ values between 0.48 and 2.05 μg mL^?1. The mixture of dihydroxy cyclohex-2-enones 4a and 4b, which was far less toxic than 2 and 3, also showed promising antiplasmodial activity and may be a possible lead for further investigation as an antiplasmodial drug.     

C<Subscript>21</Subscript> steroid derivatives from the Dai herbal medicine Dai-Bai-Jie,the dried roots of <Emphasis Type="Italic">Marsdenia tenacissima</Emphasis>, and their screening for anti-HIV activity

Twenty-three new C₂₁ steroidal glycosides, marstenacissides C1–C10 (1–10), D1–D7 (11–17) and E1–E6 (18–23), and four new C₂₁ steroids, 11α,12β-O-ditigloyl-tenacigenin C (24), 11α-O-benzoyl-12β-O-tigloyl-tenacigenin C (25), 11α-O-tigloyl-12β-O-benzoyl-tenacigenin C (26) and 11α-O-tigloyl-12β-O-benzoyl-marsdenin (27), were isolated from the Dai herbal medicine Dai-Bai-Jie, derived from the roots of Marsdenia tenacissima. The chemical structures of all compounds were established by spectroscopic techniques, including high-resolution mass spectrometry and NMR spectroscopy, as well as by comparison with reported spectral data. The anti-HIV activities of these compounds were screened, and the compounds obtained displayed inhibitory effects against HIV-1 with inhibition rates of 36.4–81.3% at 30 μM.     

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.     

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.     

Two new quinones from the roots of <Emphasis Type="Italic">Juglans mandshurica</Emphasis>

Two new quinones, 1-hydroxy-5-pentyl-anthraquinone (1) and 4-(5-hydroxy-1,4-dioxo-1,4-dihydro-naphthalen-2-ylamino)-butyric acid methyl ester (2), together with two known quinones, 5-hydroxy-2-(2-hydroxy-ethylamino)-(1,4) naphthoquinone (3) and juglone (4) were isolated from the roots of Juglans mandshurica (Juglandaceae). Their structures were elucidated on the basis of spectral data. Compound 3 was isolated from the Juglans genus for the first time. Compounds 1–4 exhibited significant cytotoxicity towards cultured MDA-MB231, HepG2 and SNU638 cells with IC₅₀ values ranging from 4.46 to 88.47 μM.     

Phenolic amides from <Emphasis Type="Italic">Tribulus terrestris</Emphasis> and their inhibitory effects on nitric oxide production in RAW 264.7 cells

A new phenolic amide, named cis-terrestriamide (7), together with ten known compounds (1–6, 8–11), were isolated from the methanolic extract of the fruits of Tribulus terrestris. The structure of 7 was elucidated on the basis of extensive analyses of 1D and 2D nuclear magnetic resonance spectroscopic and high resolution mass spectrometry data. Compounds 1, 2, 5, 6, 8, 9, and 11 exhibited inhibitory effects on the lipopolysaccharide-stimulated nitric oxide production in RAW 264.7 cells, with IC₅₀ values of 18.7–49.4 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.     

In vitro cytotoxic activity of isolated compounds from Malaysian <Emphasis Type="Italic">Calophyllum</Emphasis> species

Cancer is a leading cause of death worldwide. In our continuing search for new anticancer agents, four Malaysian Calophyllum species, namely C. castaneum, C. teysmannii, C. canum, and C. sclerophyllum, had been phytochemically studied to give compounds 1–12. All the isolated compounds were evaluated for their antiproliferative activity against nasopharyngeal (SUNE1, TW01, CNE1, HK1) and breast (HCC38, MDA-MB-231, MDA-MB-468, SKBR3) cancer cell lines via methyl thiazolyl tetrazolium cell viability assay. Among the tested compounds, isodispar B (1) showed a promising dose-dependent and a broad spectrum of cytotoxic effects on all the tested cancer cell lines; in particular, potent inhibitory activities were observed on nasopharyngeal cancer cell lines (SUNE1, TW01, CNE1, HK1), with IC₅₀ values ranging from 3.8 to 11.5 µM. In comparison with 5-fluorouracil as positive control, compound 1 was found to exhibit at least sixfold much higher activity than the standard drug used against the nasopharyngeal cell lines. Compound 1 was later found to induce apoptotic cell death in nasopharyngeal cancer cells, as evidenced by ‘Cell Death Detection’ ELISA^PLUS kit, and exhibited good cancer-specific cytotoxicity when tested with noncancerous NP460 cells. Meanwhile, compounds 2–12 displayed moderate to weak activities against the tested cancer cell lines. The findings have highlighted the therapeutic potential of compound 1 against nasopharyngeal cancer.     

A new terpene coumarin microbial transformed by <Emphasis Type="Italic">Mucor polymorphosporus</Emphasis> induces apoptosis of human gastric cancer cell line MGC-803

2′-Z auraptene (1) is a synthesized monoterpene coumarin with anticancer activity against human gastric cancer cells. In order to find new potential anticancer agent, Mucor polymorphosporus was used to transform cis-auraptene. Four new terpene coumarins with notable changes in the skeletal backbone, 2′-Z auraptene A-D (2–5), were obtained and evaluated for their antiproliferative effects against human normal gastric epithelium cells and human gastric cancer cells. These new compounds showed selective cytotoxic activity against MGC-803 cells with IC₅₀ values from 0.78?±?0.13 to 10.78?±?1.83 μM and the therapeutic index could also be significantly improved (TI?=?59.0) compared with that of 1 (TI?=?5.5). The structures of these metabolites were elucidated through extensive spectroscopic methods, and the possible biotransformation pathway of 1 by Mucor polymorphosporus was also proposed. Furthermore, the mechanism of the antiproliferative effects against MGC-803 cells of the most potent compound, 2′-Z auraptene A (2), was characterized. Annexin V/PI staining and abnormal expression of apoptosis-related protein suggested that compound 2 induces apoptosis in gastric cancer MGC-803 cells. Therefore, it is possible that compound 2 has the potential to be applied in gastric cancer therapy.     

Two new antimalarial quassinoid derivatives from the stems of <Emphasis Type="Italic">Brucea javanica</Emphasis>

Phytochemical investigation of the stems from Brucea javanica led to the isolation of two new quassinoids, brujavanol C (1) and brujavanol D (2), together with six known compounds (3–8). The chemical structures were elucidated by means of various spectroscopic methods. All the isolated compounds were evaluated for antimalarial activity against Plasmodium falciparum and compounds 6 and 7 exhibited the most potent activity against the K1 strain, with IC₅₀ values of 1.41 and 1.06 μM, respectively.