Anticholinesterase Activity of Methanolic Extract of Amorpha fruticosa Flowers and Isolation of Rotenoids and Putrescine and Spermidine Derivatives.

Five putrescine and spermidine derivatives (1-5) together with five rotenoids (6-10) were isolated from a methanolic extract of the flowers of A. fruticosa that displayed promising inhibition of 76.0 ± 1.9% for AChE and 90.0 ± 4.0% for BuChE at a concentration of 1 mg/mL. Although the anticholinesterase activities of the isolated compounds did not reach that of galantamine, molecular docking revealed that all-trans-tri-p-coumaroylspermidine and trans-trans-cis-tri-p-coumaroylspermidine showed binding poses mimicking the known inhibitor galantamine and thus could serve as model molecules in future searches for new AChE and BuChE inhibitors.

Five New Tamarixetin Glycosides from Astragalus thracicus Griseb. Including Some Substituted with the Rare 3-Hydroxy-3-methylglutaric Acid and Their Collagenase Inhibitory Effects In Vitro.

Along with the known kaempferol-3-O-α-l-rhamnopyranosyl-(1 → 2)-[6-O-(3-hydroxy-3-methylglutaryl)]-ß-d-galactopyranoside (1), five new flavonoids, containing the rarely isolated aglycon tamarixetin, were isolated from a methanolic extract of the endemic Balkan species Astragalus thracicus Griseb. Three of the new compounds are substituted with 3-hydroxy-3-methylglutaryl residue (HMG), untypical for the genus Astragalus. The compounds were identified as tamarixetin-3-O-α-l-rhamnopyranosyl-(1 → 2)-[6-O-(3-hydroxy-3-methylglutaryl)]-ß-d-galactopyranoside (2), tamarixetin-3-O-(2,6-di-O-α-l-rhamnopyranosyl)-ß-d-galactopyranoside (3), tamarixetin 3-O-ß-d-apiofuranosyl-(1 → 2)-ß-d-galactopyranoside (4), tamarixetin-3-O-ß-d-apiofuranosyl-(1 → 2)-[6-O-(3-hydroxy-3-methylglutaryl)]-ß-d-galactopyranoside (5), and tamarixetin-3-O-ß-d-apiofuranosyl-(1 → 2)-[α-l-rhamnopyranosyl-(1 → 6)]-ß-d-galactopyranoside (6). Selected compounds from A. thracicus were tested to evaluate their anticollagenase activity. The greatest effect was observed for quercetin-3-O-ß-d-apiofuranosyl-(1 → 2)-ß-d-galactopyranoside, possibly due to the presence of an ortho-dihydroxy arrangement of flavonoid ring B. The effect on collagenase and elastase was further evaluated also by in silico study, and the test compounds showed some level of in silico interaction.

Cholinesterase and Tyrosinase Inhibitory Potential and Antioxidant Capacity of Lysimachia verticillaris L. and Isolation of the Major Compounds.

OBJECTIVES: The scope of the present study was to specify the therapeutic potential for neurodegenerative diseases through evaluating cholinesterase and tyrosinase (TYR) inhibitory and antioxidant activity of Lysimachia verticillaris (LV), and to isolate the major compounds considering the most active fraction. MATERIALS AND METHODS: The methanol extract (ME) of LV and the chloroform, ethyl acetate (EtOAC), and aqueous fractions obtained from it were used for biological activity and isolation studies. The ME and all fractions were tested for their acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and TYR inhibitory and antioxidant potentials using ELISA microtiter assays. Seven major compounds were isolated from the active EtOAC fraction by semi-preparative high performance liquid chromatography. The structures of the compounds were elucidated by several spectroscopic methods. RESULTS: Marked AChE inhibitory activity was observed in the EtOAC fraction (6337±1.74%), BChE inhibitory activity in the ME and EtOAC fraction (85.84±3.01% and 83.82±3.93%), total phenol content in the EtOAC fraction (261.59±3.95 mg equivalent of gallic acid/1 g of extract) and total flavonoid contents in the EtOAC fraction (515.54±2.80 mg equivalent of quercetin/1 g of extract), and 2,2-diphenyl-1-picrylhydrazyl radical scavenging activity and ferric-reducing antioxidant power values in the aqueous and EtOAC fractions (92.54±0.67%, 92.11±0.30%; 2.318±0.054, 2.224±0.091, respectively). Accordingly, the isolation studies were carried out on the EtOAC fractions. Compounds 1-7 (gallic acid, (+)-catechin, myricetin 3-O-arabinofuranoside, myricetin 3-O-α-rhamnopyranoside, quercetin 3-O-ß-glucopyranoside, quercetin 3-O-arabinofuranoside, and quercetin 3-O-α-rhamnopyranoside, respectively) were isolated from the active EtOAC fraction. CONCLUSION: LV may be a potential herbal source for treatment of neurodegenerative diseases based on its strong antioxidant activity and significant cholinesterase inhibition similar to that of the reference.

Therapeutic potential of prenylated stilbenoid macasiamenene F through its anti-inflammatory and cytoprotective effects on LPS-challenged monocytes and microglia.

ETHNOPHARMACOLOGICAL RELEVANCE: Macaranga Thou. (Euphorbiaceae) is a large genus that comprises over 300 species distributed between Western Africa and the islands of the South Pacific. Plants of this genus have a long-standing history of use in traditional medicine for different purposes, including the treatment of inflammation. Fresh and dried leaves of certain Macaranga species (e.g. M. tanarius (L.) Müll.Arg.), have been used to treat cuts, bruises, boils, swellings, sores and covering of wounds in general. Several reports described Macaranga spp. being a rich source of polyphenols, such as prenylated stilbenoids and flavonoids, mostly responsible for its biological activity. Similarly, an abundant content of prenylated stilbenes was also described in M. siamensis S.J.Davies, species recently identified (2001) in Thailand. While the respective biological activity of the prenylated stilbenes from M. siamensis was poorly investigated to date, our recent study pointed out the interest as the natural source of several novel anti-inflammatory stilbenoids isolated from this species. AIM OF THE STUDY: This work investigated the potential anti-inflammatory effects of the stilbenoid macasiamenene F (MF) isolated from M. siamensis S.J.Davies (Euphorbiaceae) on the lipopolysaccharide (LPS)-induced inflammation-like response of monocytes and microglia, major cells involved in the peripheral and central inflammatory response, respectively. MATERIALS AND METHODS: LPS-induced stimulation of TLR4 signaling led to the activation of inflammatory pathways in in vitro models of THP-1 and THP-1-XBlue™-MD2-CD14 human monocytes, BV-2 mouse microglia, and an ex vivo model of brain-sorted mouse microglia. The ability of the stilbenoid MF to intervene in the IкB/NF-кB and MAPKs/AP-1 inflammatory cascade was investigated. The gene and protein expressions of the pro-inflammatory cytokines IL-1ß and TNF-α were evaluated at the transcription and translation levels. The protective effect of MF against LPS-triggered microglial loss was assessed by cell counting and the LDH assay. RESULTS: MF demonstrated beneficial effects, reducing both monocyte and microglial inflammation as assessed in vitro. It efficiently inhibited the degradation of IкBα, thereby reducing the NF-кB activity and TNF-α expression in human monocytes. Furthermore, the LPS-induced expression of IL-1ß and TNF-α in microglia was dampened by pre-, co-, or post-treatment with MF. In addition to its anti-inflammatory effect, MF demonstrated a cytoprotective effect against the LPS-induced death of BV-2 microglia. CONCLUSION: Our research into anti-inflammatory and protective effects of MF has shown that it is a promising candidate for further in vitro and in vivo investigations of MF interventions with respect to acute and chronic inflammation, including potentially beneficial effects on the inflammatory component of brain diseases such as stroke and Alzheimer's disease.

Parallel in vitro and in silico investigations into anti-inflammatory effects of non-prenylated stilbenoids.

Stilbenoids represent a large group of bioactive compounds, which occur in food and medicinal plants. Twenty-five stilbenoids were screened in vitro for their ability to inhibit COX-1, COX-2 and 5-LOX. Piceatannol and pinostilbene showed activity comparable to the zileuton and ibuprofen, respectively. The anti-inflammatory potential of stilbenoids was further evaluated using THP-1 human monocytic leukemia cell line. Tests of the cytotoxicity on the THP-1 and HCT116 cell lines showed very low toxic effects. The tested stilbenoids were evaluated for their ability to attenuate the LPS-stimulated activation of NF-κB/AP-1. Most of the tested substances reduced the activity of NF-κB/AP-1 and later attenuated the expression of TNF-α. The effects of selected stilbenoids were further investigated on inflammatory signaling pathways. Non-prenylated stilbenoids regulated attenuation of NF-ĸB/AP-1 activity upstream by inhibiting the phosphorylation of MAPKs. A docking study used to in silico analyze the tested compounds confirmed their interaction with NF-ĸB, COX-2 and 5-LOX.

Irreversible Cysteine-Selective Protein Labeling Employing Modular Electrophilic Tetrafluoroethylation Reagents.

Fluoroalkylation reagents based on hypervalent iodine are widely used to transfer fluoroalkyl moieties to various nucleophiles. However, the transferred groups have so far been limited to simple structural motifs. We herein report a reagent featuring a secondary amine that can be converted to amide, sulfonamide, and tertiary amine derivatives in one step. The resulting reagents bear manifold functional groups, many of which would not be compatible with the original synthetic pathway. Exploiting this structural versatility and the known high reactivity toward thiols, the new-generation reagents were used in bioconjugation with an artificial retro-aldolase, containing an exposed cysteine and a reactive catalytic lysine. Whereas commercial reagents based on maleimide and iodoacetamide labeled both sites, the iodanes exclusively modified the cysteine residue. The study thus demonstrates that modular fluoroalkylation reagents can be used as tools for cysteine-selective bioconjugation.

Nucleophilic Tetrafluoroethylation Employing in Situ Formed Organomagnesium Reagents.

Tetrafluoroalkyl bromides are metalated with equimolar iPrMgCl·LiCl (Turbo Grignard) to form organomagnesium compounds which are stable at low temperatures and react with various electrophiles (aldehydes, ketones, CO2, cyclic sulfate and sulfamidate, N-sulfonylimines, nitrone, chlorophosphate, nonaflyl azide) to afford novel functionalized tetrafluoroethylene-containing products. Ease of operation, excellent selectivity, high nucleophilicity, and enhanced stability of the reactive species together with a broad substrate scope comprise a highly attractive nucleophilic tetrafluoroethylation protocol affording unique synthetic building blocks.

The Chemical Composition of Achillea wilhelmsii C. Koch and Its Desirable Effects on Hyperglycemia, Inflammatory Mediators and Hypercholesterolemia as Risk Factors for Cardiometabolic Disease.

This study was done to identify the content compounds of Achillea wilhelmsii (A. wilhelmsii) and to evaluate its hypoglycemic and anti-hypercholesterolemic activity and effect on inflammatory mediators. The extracts and fractions of A. wilhelmsii were thoroughly analyzed using high performance liquid chromatography (HPLC), and the total content of phenols and flavonoids was determined. The hypoglycemic activity was evaluated in vivo using alloxan-induced diabetic mice. The effect upon inflammatory mediators was evaluated in vitro using the human monocytic leukemia cell line (THP-1). The anti-hypercholesterolemic activity was evaluated in vitro using the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase assay kit. The water extract (WE)-treated group showed the highest reduction in the fasting blood glucose levels (FBGL). The chloroform fraction (CF) and ethyl acetate fraction (EAF) both showed a significant ability to reduce the secretion of tumor necrosis factor alpha (TNF-α). The EAF, however, also attenuated the levels of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). The CF showed the most significant 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) inhibition activity. The five main compounds in the CF were isolated and identified. Out of the five compounds in the CF, 1ß,10ß-epoxydesacetoxymatricarin (CP1) and leucodin (CP2) showed the highest anti-hypercholesterolemic potential. A molecular docking study provided corresponding results.

Synthesis and reactivity of aliphatic sulfur pentafluorides from substituted (pentafluorosulfanyl)benzenes.

Oxidation of 3- and 4-pentafluorosulfanyl-substituted anisoles and phenols with hydrogen peroxide and sulfuric acid provided a mixture of SF5-substituted muconolactone, maleic, and succinic acids. A plausible mechanism for the formation of the aliphatic SF5 compounds was presented and their chemical reactivity was investigated. SF5-substituted para-benzoquinone was synthesized; its oxidation led to an improved yield of 2-(pentafluorosulfanyl)maleic acid. The reaction of SF5-substituted maleic anhydride and para-benzoquinone with cyclopentadiene afforded the Diels-Alder adducts. Decomposition of 3-(pentafluorosulfanyl)muconolactone in acidic, neutral and basic aqueous media was investigated and the decarboxylation of 2-(pentafluorosulfanyl)maleic acid provided 3-(pentafluorosulfanyl)acrylic acid.

Expanding the Scope of Hypervalent Iodine Reagents for Perfluoroalkylation: From Trifluoromethyl to Functionalized Perfluoroethyl.

A series of new hypervalent iodine reagents based on the 1,3-dihydro-3,3-dimethyl-1,2-benziodoxole and 1,2-benziodoxol-3-(1H)-one scaffolds, which contain a functionalized tetrafluoroethyl group, have been prepared, characterized, and used in synthetic applications. Their corresponding electrophilic fluoroalkylation reactions with various sulfur, oxygen, phosphorus, and carbon-centered nucleophiles afford products that feature a tetrafluoroethylene unit, which connects two functional moieties. A related λ(3) -iodane that contains a fluorophore was shown to react with a cysteine derivative under mild conditions to give a thiol-tagged product that is stable in the presence of excess thiol. Therefore, these new reagents show a significant potential for applications in chemical biology as tools for fast, irreversible, and selective thiol bioconjugation.

C-Geranylated Flavanones from Paulownia tomentosa Fruits as Potential Anti-inflammatory Compounds Acting via Inhibition of TNF-α Production.

Eleven new C-geranylated flavonoids, tomentodiplacones L, M, and N (1, 2, 10), tomentodiplacol B (3), 3',4'-O-dimethyl-5'-hydroxydiplacone (4), mimulones F, G, and H (5, 6, 7), paulowniones A (8) and B (9), tomentone (11), and 3',4',5'-trimethoxyflavanone (12), together with 11 known flavonoids (13-23), were isolated from fruits of Paulownia tomentosa. The structures of the compounds isolated were determined by spectroscopic data interpretation. The ability of compounds 1-23, together with the nonprenylated flavanones eriodictyol (24) and naringenin (25), to reduce the production of the pro-inflammatory cytokine TNF-α in THP-1 cells after bacterial lipopolysaccharide stimulation was evaluated using an in vitro screening test. The preliminary structure-activity relationships of these derivatives were also studied, and the correlation of their TNF-α inhibitory activity with their lipophilicity was investigated. The mechanism of action of compounds with significant antiphlogistic potential (4, 7, 10, 14, 22) was investigated. These compounds reduced both the secretion of TNF-α and the level of its corresponding mRNA. Compounds 4, 7, 10, 14, and 22 inhibited the nuclear translocation of NF-κB, which controls the expression of TNF-α, by blocking the degradation of IκB.

Experimental and theoretical perspectives of the Noyori-Ikariya asymmetric transfer hydrogenation of imines.

The asymmetric transfer hydrogenation (ATH) of imines catalyzed by the Noyori-Ikariya [RuCl(η6-arene)(N-arylsulfonyl-DPEN)] (DPEN=1,2-diphenylethylene-1,2-diamine) half-sandwich complexes is a research topic that is still being intensively developed. This article focuses on selected aspects of this catalytic system. First, a great deal of attention is devoted to the N-arylsulfonyl moiety of the catalysts in terms of its interaction with protonated imines (substrates) and amines (components of the hydrogen-donor mixture). The second part is oriented toward the role of the η6-coordinated arene. The final part concerns the imine substrate structural modifications and their importance in connection with ATH. Throughout the text, the summary of known findings is complemented with newly-presented ones, which have been approached both experimentally and computationally.

Practical aspects and mechanism of asymmetric hydrogenation with chiral half-sandwich complexes.

This review is oriented toward the asymmetric transfer hydrogenation (ATH) of imines regarding mostly fundamental, yet important topics from the practical point of view. Development of analytical methods for the monitoring of ATH (i.e., kinetics and stereoselectivity) belongs to those topics, as well as studies on the influence of reaction conditions and structural variations on the reaction performance. The second part is devoted to the reaction mechanism with the emphasis on imine ATH and catalyst behaviour under acidic conditions. The review also addresses the asymmetric hydrogenation (AH) of ketones and imines using molecular hydrogen and the application of ATH in pharmaceutical projects. The contributions of our group to each area are included.

New insight into the role of a base in the mechanism of imine transfer hydrogenation on a Ru(II) half-sandwich complex.

Asymmetric transfer hydrogenation (ATH) of cyclic imines using [RuCl(η(6)-p-cymene)TsDPEN] (TsDPEN = N-tosyl-1,2-diphenylethylenediamine) was tested with various aliphatic (secondary, tertiary) and aromatic amines employed in the HCOOH-base hydrogen donor mixture. Significant differences in reaction rates and stereoselectivity were observed, which pointed to the fact that the role of the base in the overall mechanism could be more significant than generally accepted. The hydrogenation mixture was studied by nuclear magnetic resonance (NMR), Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) and vibrational circular dichroism (VCD) with infrared spectroscopy. The results suggested that the protonated base formed an associate with the active ruthenium-hydride species, most probably via a hydrogen bond with the sulfonyl group of the complex. It is assumed that the steric and electronic differences among the bases were responsible for the results of the initial ATH experiments.

Opportunities offered by chiral η6-arene/N-arylsulfonyl-diamine-RuII catalysts in the asymmetric transfer hydrogenation of ketones and imines.

Methods for the asymmetric transfer hydrogenation (ATH) of ketones and imines are still being intensively studied and developed. Of foremost interest is the use of Noyori's [RuCl(η6-arene)(N-TsDPEN)] complexes in the presence of a hydrogen donor (i-PrOH, formic acid). These complexes have found numerous practical applications and have been extensively modified. The resulting derivatives have been heterogenized, used in ATH in water or ionic liquids and even some attempts have been made to approach the properties of biocatalysts. Therefore, an appropriate modification of the catalyst that suits the specific requirements for the reaction conditions is very often readily available. The mechanism of the reaction has also been explored to a great extent. Model substrates, acetophenone (a ketone) and 6,7-dimethoxy-1-methyl-3,4-dihydroisoquinoline (an imine), are both reduced by this Ru catalytic system with almost perfect selectivity. However, in each case the major product is a different enantiomer (S- for an alcohol, R- for an amine when the S,S-catalyst is used), which demanded an in-depth mechanistic investigation. Full-scale molecular modelling of this system enabled us to visualize the plausible 3D structures of the transition states, allowing the proposition of a viable explanation of previous experimental findings.

Performance of phased rotation, conformation and translation function: accurate protein model building with tripeptidic and tetrapeptidic fragments.

The automatic building of protein structures with tripeptidic and tetrapeptidic fragments was investigated. The oligopeptidic conformers were positioned in the electron-density map by a phased rotation, conformation and translation function and refined by a real-space refinement. The number of successfully located fragments lay within the interval 75-95% depending on the resolution and phase quality. The overlaps of partially located fragments were analyzed. The correctly positioned fragments were connected into chains. Chains formed in this way were extended directly into the electron density and a sequence was assigned. In the initial stage of the model building the number of located fragments was between 60% and 95%, but this number could be increased by several cycles of reciprocal-space refinement and automatic model rebuilding. A nearly complete structure can be obtained on the condition that the resolution is reasonable. Computer graphics will only be needed for a final check and small corrections.