Nitric Oxide Production Inhibitory Eudesmane‐Type Sesquiterpenoids from Artemisia argyi

Six new eudesmane‐type sesquiterpene derivatives, artemargyinins A–F were isolated from the leaves of Artemisia argyi. Their structures were elucidated based on the extensive analysis of spectroscopic data. Artemargyinins A–F feature a lactone ring‐opening eudesmane‐type sesquiterpene with an isoprenoid group at C(8). All compounds were tested for their inhibitory effects on lipopolysaccharide‐induced nitric oxide (NO) production in RAW264.7 macrophages. Artemargyinins A–F showed more potent NO production inhibitory activity with IC₅₀ values ranging from 7.66±0.53 to 61.19±2.54 μM than the positive control quercetin (IC₅₀=74.34±1.39 μM). Among them, artemargyinins C and D exhibited strong inhibitory activity with IC₅₀ values of 8.08±0.21 and 7.66±0.53 μM, respectively.     

Five New Phenolic Glycosides from Viburnum luzonicum

Viburnum luzonicum is widely distributed in China. Its branch extracts showed potential α-amylase and α-glucosidase inhibitory activities. In order to discover new bioactive constituents, five undescribed phenolic glycosides, viburozosides A−E ( 1 – 5 ), were obtained by bioassay-guided isolation coupled with HPLC-QTOF-MS/MS analysis. Their structures were elucidated by spectroscopic analyses, including 1D NMR, 2D NMR, ECD, and ORD. All compounds were tested for their α-amylase and α-glucosidase inhibitory potency. Compound 1 showed significantly competitive inhibition against α-amylase (IC₅₀=17.5 μM) and α-glucosidase (IC₅₀=13.6 μM).     

Inhibitory Effect of Aryl Thienyl-Ketones and - Thioketones on Arachidonic Acid-induced Malondialdehyde Formation in Human Platelets: Biological Data and Molecular Modelling

Abstract

A series of anti-thrombotic aryl thienyl-ketones and -thioketones was assayed in vitro for their inhibitory effect on malondialdehyde (MDA) production induced by arachidonic acid in human platelets. For several compounds MDA formation was strongly inhibited indicating that the anti-platelet target was situated on the cyclooxygenase pathway. A comparison between the inhibition constant K₁ and the IC₅₀ values revealed competitive inhibition kinetics. The molecular structure of one active compound was analysed by X-ray diffraction and theoretical calculations to provide information on its electronic and lipophilic properties.     

ent-Herqueidiketal and epi-Peniciherqueinone Isolated from a Mushroom Derived Fungus Penicillium herquei YNJ-35

A new polyaromatic metabolite, ent-herqueidiketal ( 1 ), and a new phenalenone derivative, epi-peniciherqueinone ( 2 ), along with twelve known compounds 3 – 14 , were isolated from the fungus Penicillium herquei YNJ-35, a symbiotic fungus of Pulveroboletus brunneopunctatus collected from Nangunhe Nature Reserve, Yunnan Province, China. The structures of 1 – 14 and the absolute configurations of 1 and 2 were determined by their spectroscopic data or by their single-crystal X-ray diffraction analysis or optical rotation values. Compound 1 showed strong antibacterial activity against Staphylococcus aureus (ATCC 29213) with minimum inhibitory concentration (MIC) of 8 μg/mL. In the cytotoxicity assays, compound 1 showed weak inhibitory activity against breast cancer MCF-7 and mice microglial BV2 cells with half maximal inhibitory concentration (IC₅₀) of 17.58 and 29.56 μM; compound 14 showed stronger cytotoxicity against BV2 and MCF-7 cells with IC₅₀ values of 6.57 and 10.26 μM.     

Four New Flavonoid C-Glycosides Isolated from Achyranthes aspera and Their Nitric Oxide Production Inhibitory Activities

A chemical study of the methanol extract of the aerial parts of Achyranthes aspera led to the isolation of four new flavonoid C-glycosides ( 1 – 4 ) along with eight known analogs ( 5 – 12 ). Their structures were elucidated by a combination of spectroscopic data analysis, HR-ESI-MS, 1D and 2D NMR spectra. All the isolates were evaluated their NO production inhibitory activity in LPS-activated RAW264.7 cells. Compounds 2 , 4 , and 8 – 11 showed significant inhibition with IC₅₀ values ranging from 25.06 to 45.25 μM, compared to that of the positive control compound, L-NMMA, IC₅₀ value of 32.24 μM, whereas the remaining compounds were weak inhibitory activity with IC₅₀ values over 100 μM. This is the first report of 7 from Amaranthaceae family, and 11 from the genus Achyranthes.     

1H Quantitative NMR analyses of β-asarone and related compounds for quality control of Acorus rhizome herbal drugs in terms of the effects of their constituents on in vitro acetylcholine esterase activity

We used quantitative nuclear magnetic resonance analyses to measure the contents of major constituents of Acorus rhizome materials used as herbal drugs. The inhibitory effects of crude n-hexane extracts and their individual constituents on in vitro acetylcholine esterase activity were evaluated. The crude extracts had unexpectedly weak inhibitory effects (46–64% inhibition at 1.0 mg/mL), despite the high content (46–64%) of β-asarone, which independently had a potent effect (IC₅₀ 2.9 µM [0.61 µg/mL]). Further investigation revealed participation of eudesmin A, a lignan constituent, in the suppression of the inhibitory effect of β-asarone.     

Synthesis of 2-Chloro-6-aryloxy- and 2-Chloro-6-alkoxyarylpurines and Their Properties in the Purine Nucleoside Phosphorylase (PNP) System

Abstract

A series of 2-chloro-6-aryloxy- and 2-chloro-6-alkoxyarylpurines was synthesized and their kinetic properties in the purine nucleoside phosphorylase (PNP) system were determined. All compounds showed inhibitory activity (IC₅₀ in the range 0.5-76 μM) vs. hexameric (“high-molecular weight”) PNP from E. coli. By contrast, no inhibition vs. trimeric Cellulomonas PNP was detected.     

Synthesis of chiral pyrazolo[4,3-e][1,2,4]triazine sulfonamides with tyrosinase and urease inhibitory activity

A new series of sulfonamide derivatives of pyrazolo[4,3-e][1,2,4]triazine with chiral amino group has been synthesized and characterized. The compounds were tested for their tyrosinase and urease inhibitory activity. Evaluation of prepared derivatives demonstrated that compounds (8b) and (8j) are most potent mushroom tyrosinase inhibitors whereas all of the obtained compounds showed higher urease inhibitory activity than the standard thiourea. The compounds (8a), (8f) and (8i) exhibited excellent enzyme inhibitory activity with IC₅₀ 0.037, 0.044 and 0.042?μM, respectively, while IC₅₀ of thiourea is 20.9?μM.     

Design,synthesis and biological evaluation of novel 1H-1,2,4-triazole,benzothiazole and indazole-based derivatives as potent FGFR1 inhibitors viafragment-based virtual screening

Abstract

Fibroblast growth-factor receptor (FGFR) is a potential target for cancer therapy. We designed three novel series of FGFR1 inhibitors bearing indazole, benzothiazole, and 1H-1,2,4-triazole scaffold via fragment-based virtual screening. All the newly synthesised compounds were evaluated in vitro for their inhibitory activities against FGFR1. Compound 9d bearing an indazole scaffold was first identified as a hit compound, with excellent kinase inhibitory activity (IC₅₀ = 15.0?nM) and modest anti-proliferative activity (IC₅₀ = 785.8?nM). Through two rounds of optimisation, the indazole derivative 9?u stood out as the most potent FGFR1 inhibitors with the best enzyme inhibitory activity (IC₅₀ = 3.3?nM) and cellular activity (IC₅₀ = 468.2?nM). Moreover, 9?u also exhibited good kinase selectivity. In addition, molecular docking study was performed to investigate the binding mode between target compounds and FGFR1.     

Nitric Oxide Production‐Inhibitory Activity of Limonoids from Azadirachta indica and Melia azedarach

Seventy‐three limonoids isolated from three Meliaceae plants, Azadirachta indica, A. indica var. siamensis, and Melia azedarach, or semi‐synthesized from the Meliaceae limonoids, were evaluated for their inhibitory activity against nitric oxide (NO) production in mouse macrophage RAW 264.7 cells induced by lipopolysaccharide (LPS), as a primary screening test for anti‐inflammatory agents. Of the compounds tested, 21 compounds exhibited inhibitory activity (IC₅₀ 4.6 – 58.6 μm ) without any significant toxicity (IC₅₀ > 100 μm ) which were more potent than l ‐NMMA (NO‐production inhibitory activity, IC₅₀ 65.6 μm ; cytotoxicity, IC₅₀ > 100 μm ), and among which, nine compounds, i.e., 17‐hydroxy‐15‐methoxynimbocinol ( 6 ), ohchinin ( 20 ), 1‐cis‐cinnamoyl‐1‐decinnamoylohchinin ( 24 ), salannin ( 27 ), methyl nimbidate ( 32 ), isosalannin ( 55 ), nimbolinin D ( 58 ), mesendanin E ( 69 ), and 7‐deacetylgedunin ( 73 ) exhibited potent inhibitory activity (IC₅₀ 4.6 – 29.3 μm ). In particular, compounds 6 (IC₅₀ 7.3 μm ), an azadirone‐type limonoid, and 73 (IC₅₀ 4.6 μm ), a gedunin‐type limonoid, exhibited remarkable activity. Western blot analysis revealed that 27 and 73 reduced the expression levels of the inducible NO synthase and cyclooxygenase‐2 proteins in a concentration‐dependent manner. These findings suggest that limonoids of A. indica, A. indica var. siamensis, and M. azedarach, and their semi‐synthetic derivatives may be effective against inflammation.     

Inhibition of phospholipid methylation in isolated rat hepatocytes by analogues of adenosine and S-adenosylhomocysteine

Phospholipid methylation in isolated hepatocytes was inhibited in the presence of 3-deazaadenosine (ID₅₀ = 1.7 μM) 9-β-d-arabinofuranosyladenine (ID₅₀ = 6.0 μM), S-tubercidinylhomocysteine (ID₅₀ = 30 μM), and 5′-deoxy-5′-isobutylthioadenosine (ID₅₀ = 177 μM). A transient inhibitory effect was observed with adenosine, whereas S-adenosyl-l-homocysteine and Sinefungin were essentially without effect. The inhibition of phospholipid methylation by S-tubercidinylhomocysteine and 9-β-d-arabinofuranosyladenine showed a lag-phase, whereas the effect of the other inhibitors was apparent within a few minutes. Cells exposed to 9-β-d-arabinofuranosyladenine or 3-deazaadenosine accumulated large amounts of AdoHcy, and adenosine induced a transient increase in the AdoHcy level. In addition, 3-deazaadenosine served as a precursor for the formation of S-3-deazaadenosylhomocysteine, which accumulated rapidly in cells exposed to this agent. The inhibitory effects of 3-deazaadenosine, 9-β-d-arabinofuranosyladenine and adenosine could be explained by the increase in total nucleosidylhomocysteine induced by these agents. In contrast, only a slight (less than 2-fold) increase in S-adenosyl-l-homocysteine content was observed in hepatocytes treated with 5′-deoxy-5′-isobutylthioadenosine, and this metabolic effect could not explain the inhibition of phospholipid methylation induced by this agent. None of the compounds tested reduced the amount nor the specific radioactivity of S-adenosylmethionine. Biological processes determining the inhibitory effects of adenosine, S-adenosyl-l-homocysteine and their analogues on phospholipid methylation in intact cells are discussed.     

Five New Oleanane Triterpene Saponins from Camellia petelotii and Their Alpha-glucosidase Inhibitory Activity

Five new triterpenoid glycosides, named campetelosides A–E ( 1–5 ), together with three known compounds, chikusetsusaponin IVa ( 6 ), umbellatoside B ( 7 ), and silvioside E ( 8 ) were isolated from the leaves of Camellia petelotii (Merr.) Sealy. Their chemical structures were determined by interpretations of HR-ESI-MS and NMR spectra. In addition, compounds 1–8 were evaluated for their α-glucosidase inhibitory effects. Compounds 1–3 significantly showed α-glucosidase inhibitory activity with IC₅₀ values of 166.7±6.0, 45.9±2.6, and 395.3±10.5 μM, respectively, compared to that of the positive control, acarbose, with an IC₅₀ value of 200.4±10.5 μM.     

A potential role of alkaloid extracts from Salsola species (Chenopodiaceae) in the treatment of Alzheimer's disease

From the aerial parts of Salsola oppositofolia, S. soda and S. tragus an alkaloid extract was obtained and tested to evaluate antioxidant and anti-cholinesterase activities. The in vitro study of the antioxidant activity by the DPPH method revealed a significant activity of Salsola alkaloid extracts with IC₅₀ values ranging from 16.30 μg/mL for S. oppositifolia to 26.17 μg/mL for S. tragus. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities were evaluated. S. tragus alkaloid extract exerted the highest inhibitory activity against AChE (IC₅₀ of 30.2 μg/mL) and BChE (IC₅₀ of 26.5 μg/mL). Interestingly, S. soda and S. oppositifolia exhibited a selective inhibitory activity against BChE with IC₅₀ values of 34.3 μg/mL and 32.7 μg/mL, respectively. Tetrahydroisoquinoline alkaloids were identified and quantified by GC/MS analysis.     

Horsfielenigans A and B,Two Rearranged Lignans with Anti-Inflammatory Effects from Horsfieldia kingii

Seven lignans were isolated from 70 % aqueous acetone extracts of the twigs and leaves of Horsfieldia kingii. Among these, new compounds 1 – 3 were identified by spectroscopic techniques, with horsfielenigans A and B ( 1 and 2 ) being particularly noteworthy for their rare β-benzylnaphthalene skeleton, where compound 1 contains an oxabicyclo[3,2,1]octane moiety. In vitro evaluation of bioactivity against nitric oxide (NO) production in LPS-activated RAW264.7 macrophages revealed inhibitory effects by 1 (IC₅₀=7.3 μM) and 2 (IC₅₀=9.7 μM).     

In Vitro Survey of α-Glucosidase Inhibitory Food Components

A survey of food components with α-glucosidase (AGH) inhibitory activity was conducted to identify a prophylactic effect for diabetes in food. Sardine muscle hydrolyzed by alkaline protease showed potent activity (IC₅₀ = 48.7mg/ml) as well as green and oolong teas (IC₅₀ = 11.1 and 11.3mg/ml, respectively). Furthermore, hydrolyzates prepared by various proteases gave differing AGH inhibitory activity. DEAE-Sephadex chromatography of the alkaline protease hydrolyzate eluted potent AGH inhibitors (IC₅₀ = 15.6mg/ml) with a 50 mm phosphate buffer (pH 7.0) containing 0.3 m NaCl, and their subsequent separation by HPLC in an ODS column showed that there were some inhibitors possessing primary amino groups. This indicates that they would have been high anionic and peptidic compounds.     

Some Physical and Chemical Properties of Nuclease P1

The inhibitory action of compressed hydrocarbon gases on the growth of the yeast Saccharomyces cerevisiae was investigated quantitatively by microcalorimetry. Both the 50% inhibitory pressure (IP₅₀) and the minimum inhibitory pressure (MIP), which are regarded as indices of the toxicity of hydrocarbon gases, were determined from growth thermograms. Based on these values, the inhibitory potency of the hydrocarbon gases increased in the order methane << ethane < propane < i-butane < n-butane. The toxicity of these hydrocarbon gases correlated to their hydrophobicity, suggesting that hydrocarbon gases interact with some hydrophobic regions of the cell membrane. In support of this, we found that UV absorbing materials at 260 nm were released from yeast cells exposed to compressed hydrocarbon gases. Additionally, scanning electron microscopy indicated that morphological changes occurred in these cells.     

Cytotoxicity and DNA Topoisomerase Inhibitory Activity of Benz[f]indole-4,9-dione Analogs

A series of benz[f]indole-4,9-diones, based on the antitumor activity of 1,4-naphthoquinone, were synthesized and evaluated for their cytotoxic activity in cultured human cancer cell lines A549 (lung cancer), Col2 (colon cancer), and SNU-638 (stomach cancer), and also for the inhibition of human DNA topoisomerases I and II activity in vitro. Several compounds including 2-amino-3-ethoxycarbonyl-N-methyl-benz[f]indole-4,9-dione showed a potential cytotoxic activity judged by IC₅₀<20.0 μg/ml in the panel of cancer cell lines. Especially, 2-hydroxy-3-ethoxycarbonyl-N-(3,4-dimethylphenyl)-benz[f]indole-4,9-dione had potential selective cytotoxicity against lung cancer cells (IC₅₀=0.4 μg/ml)) compared to colon (IC₅₀>20.0 μg/ml) and stomach (IC₅₀>20.0 μg/ml) cancer cells. To further investigate the cytotoxic mechanism, the effects of test compounds on DNA topoisomerase I and II activities were used. In a topoisomerase I-mediated relaxation assay using human placenta DNA topoisomerase I and supercoiled pHOTI plasmid DNA, 2-amino-3-ethoxycarbonyl-N-(4-fluorophenyl)-benz[f]indole-4,9-dione had the most potent inhibitory activity among the compounds tested. However, most of the compounds showed only weak inhibition of the DNA topoisomerase II-mediated KDNA (Kinetoplast DNA) decatenation assay, except for 2-amino-3-ethoxycarbonyl-N-(4-methylphenyl)-benz[f]indole-4,9-dione and 2-amino-3-ethoxycarbonyl-N-(2-bromoehtyl)-benz[f]indole-4,9-dione with a moderate inhibitory activity. These results suggest that several active compounds had relatively selective inhibitory activity against toposiomearse I compared to toposiomerase II. No obvious correlation was observed between the cytotoxicity of the individual compound and the inhibitory activity of DNA relaxation and decatenation by topoisomerase I and II, respectively, in vitro.     

Synthesis of salicyl-peptides and their effect on human platelet aggregationin vitro

Summary A series of leucine dipeptide amides containing at their N-terminal amino group the salicyl-residue [(o)-RO-C₆H₄-CO-, where R=H or CH₃CO] have been synthesized by conventional solution techniques and tested for their inhibitory activity on human platelet aggregationin vitro induced by collagen, ADP or adrenaline. The salicyl-peptide (o)-HO-C₆H₄-CO-Leu-Asp(OBzl)-NH₂ was found to exert strong inhibitory activity on platelet aggregation induced by collagen with an IC₅₀ value 4.5 mM. The corresponding dipetide H₂N-Leu-Asp(OVzl)-NH₂ was also examined and was found to be less active, indicating that the presence of the lipophilic-benzyl ester group in combination with the salicyl group enhance the inhibitory activity. All the other salicyl-peptides examined either didn't show any inhibitory or aggregatory activity or a slight inhibition at the concentration of 9–10 mm.The abbreviations used are in accordance with the rules of IUPAC-IUB Joint Commission on Biochemical Nomenclature: Eur J Biochem (1984) 138: 9–37; J Biol Chem (1989) 264: 663–673. Additional abbreviations are: ADP adenosine diphosphate - Boc tert-butyloxycarbonyl - Bzl benzyl - DIEA N,N-diisopropylethylamine - DMSO dimethyl sulfoxide - DMF N,N-dimethylformamide - EtOAc ethyl acetate - FCC flash column chromatography - IC₅₀ molar concentration of salicyl-peptide for 50% inhibition of platelet aggregation - iso-BCF isobutyl chloroformate - NMM N-methylmorpholine - PyBOP (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate - TLC thin layer chromatography - TMS tetramethylsilane     

Assessment of chemically characterised Abelmoschus moschatus Medik. seed essential oil as shelf life enhancer of herbal raw materials based on antifungal,antiaflatoxigenic and antioxidant efficacy

The study reports fungal biodeterioration of herbal raw materials of Adhatoda vasica Nees and Withania somnifera Dunal and assessment of Abelmoschus moschatus Medik seed essential oil (AMEO) as antifungal, antiaflatoxigenic, and antioxidant. Seven fungal species belonging to three genera were isolated from Adhatoda vasica leaves and Withania somnifera roots. The minimum inhibitory, fungicidal, and aflatoxin inhibitory concentrations of AMEO were found to be 1750, 5000, and 1250 ppm, respectively, against A. flavus LHP-WS-1, isolated from W. somnifera. The effect of AMEO over ergosterol content in the plasma membrane was assessed to test the mode of action on A. flavus. AMEO also exhibited broad fungitoxicity at its minimum inhibitory concentration (MIC) and strong antioxidant property through 2,2-diphenyl-1-picrylhydrazyl (DPPH) analysis having IC₅₀ value equal to 0.325 μL/mL. In view of strong antifungal, antiaflatoxigenic, and antioxidant activity, the AMEO may be recommended as botanical preservative for herbal raw materials in order to enhance their shelf life and to maintain their quality.     

New Guaiane-Type Sesquiterpene and Norsesquiterpene from Alisma plantago-aquatica and Their Xanthine Oxidase Inhibitory Activity

A new sesquiterpene ( 1 ) and a new norsesquiterpene ( 2 ) belonging guaiane-type skeleton together with six known compounds ( 3 – 8 ) were isolated from the rhizomes of Alisma plantago-aquatica. Their structures were determined by HR-ESI-MS, 1D and 2D NMR spectroscopic methods. Absolute configurations of new compounds were established by experimental and TD-DFT computational ECD spectra. Compounds 1 – 8 exhibited xanthine oxidase inhibitory activity with their IC₅₀ values in range of 9.4–66.7 μM. The sesquiterpenoids 1 – 5 displayed the inhibitory activity and hence they could be potential xanthine oxidase inhibitors from A. plantago-aquatica.