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A self-catalyzed aza-Henry addition of ethyl nitroacetate on N-alkyl trifluoromethyl aldimines was reported to synthesize β-amino α-nitro trifluoromethyl esters, precursors of α,β-diamino acid derivatives. In the presence of a resident chiral center on the imine nitrogen, the use of a suitable Lewis acid leads to a good stereofacial control, always resulting from a nucleophilic unlike attack. By starting from optically pure N-protected trifluoromethyl aldimines or directly from N-α-amino ester trifluoromethyl aldimines, small ψ[CH(CF3)NH]-peptidomimetic backbones can be achieved in which a new primary amine function represents a possible center for synthetic extension. Finally, a very interesting, and never observed before, palladium-catalyzed syn β-elimination occurred, leading to the selective nitro group reduction reaction on the syn-α-amino ester functionalized aza-Henry adducts and obtaining more stable optically pure trifluoromethyl conjugated imines. [ABSTRACT FROM AUTHOR]

The goal of this study was to develop an optimized drug delivery carrier for oral mucosa applications able to release in situ bioactive molecules by using biopolymeric materials. Among them chitosan and poly(lactic-co-glycolic acid) (PLGA) have gained considerable attention as biocompatible carriers able to improve the delivery of active agents. The formulation of such vehicles in the form of nanoparticles (NPs) could permit to exploit the peculiar properties of nanomaterials in order to enhance the efficacy of active agents. Chitosan (CS) and PLGA chlorexidine dihydrochloride (CHX)-loaded NPs were synthesized by ionotropic gelation and osmosis based methodology respectively. In order to facilitate NPs adhesion on human dental surfaces, two different strategies were employed: PLGA particles with an external shell of CS to produce a positive surface charge allowing CHX loaded PLGA NPs to interact with the negative charged dental surfaces, while CS particles were functionalized with peptidomimetic derivative glutathione (GSH). The morphology was investigated by scanning electron microscopy. A sustained release profile of CHX from CS NPs was achieved. CS-based NPs adhered on human tooth surfaces in a simulated brushing and rinsing process and their in vitro toxicity evaluation on Human Gingival Fibroblasts (HGFs) was between 20 and 60% in all experimental conditions. Thanks to their adhesion properties and low cytotoxicity, the synthesized CS-based formulations may be efficiently exploited for therapy purposes or to enhance in vivo dental care (i.e. preparation of toothpastes or other cosmetics for daily oral care). [ABSTRACT FROM AUTHOR]

Hypericum perforatum L. is a medicinal plant commonly used worldwide for the treatment of mild and moderate depression due to its wide range of bioactive compounds. H. perforatum regenerated roots have been proposed as an efficacious in vitro system to biosynthesize pharmaceutically useful secondary metabolites. In the present study, a metabolomic platform, which integrates an nuclear magnetic resonance (NMR)-based metabolic profiling and analysis of variance-simultaneous component analysis (ASCA), has been applied in order to characterize the changes of the primary and secondary metabolism of H. perforatum regenerated roots induced by an achieved high biomass density in a confined growth environment or in response to chitosan treatment.The ASCA modelling applied to NMR-based metabolic profiling allowed to recognize the effects due to biomass growth rate changes and chitosan treatment. With an high biomass density, associated to a decelerating biomass growth rate, the levels of tryptophan, fructose, shikimic acid, and epicatechin increased, whereas γ-aminobutyric acid and histidine decreased. In response to chitosan elicitation, the biomass growth was arrested and valine, isoleucine, glutamine, γ-aminobutyric acid, fructose, sucrose, polyunsaturated fatty acids, epicatechin, xanthones, dimethylallyl-pyrophosphate, and stigmasterol levels increased, while histidine levels decreased. The metabolic profiling of regenerated roots shows how the cultures respond to different stress conditions: production of epicatechin in response to high biomass density and production of epicatechin, xanthones and isoprenoids in response to chitosan-treatment. This approach can be applied to define suitable protocols to produce the desired secondary metabolites with different bioactivities. [ABSTRACT FROM AUTHOR]

Chiral ( R)-1-phenylethylamine was successfully employed in a tandem aza-Henry addition-reduction reaction to give chiral β-nitro α-trifluoromethyl amines. A subsequent coupling reaction with N-Boc-protected amino acids leads to obtain optically pure CF-modified dipeptides carrying two different N-protecting groups. These peptidomimetic units are characterized by the presence of the [CH(CF)NH] group as mimetic of the natural [CONH] peptidic bond and can be used for the synthesis of more complex CF-modified peptides after selective deprotection of one of the two amine functions. 2D NMR spectral analyses were employed to determine the absolute configurations of all newly synthesized chiral compounds. [ABSTRACT FROM AUTHOR]

Highlights: [•] Hydrophilic gold nanoparticles interacts with dexamethasone. [•] Dexamethasone interacts with AuNPs through fluorine atom. [•] Loading and release study of water insoluble drugs. [ABSTRACT FROM AUTHOR]

Abstract: Background: Aging is characterized by derangements in multiple metabolic pathways that progressively constrict the homeostatic reserve (homeostenosis). The signature of metabolic alterations that accompany aging can be retrieved through the metabolomic profiling of biological fluids. Objective: To characterize the age-related changes in urinary and fecal metabolic profiles of BALB/c mice through a 1H nuclear magnetic resonance (NMR)-based metabolomic approach. Methods: Young (n=19) and old (n=13) male BALB/c mice were fed ad libitum standard laboratory chow. Twenty four-hour feces and urine were collected using metabolic cages and analyzed by high-resolution 1H NMR spectroscopy combined with multivariate statistical analyses. Results: An age-related metabolic phenotype was detected both in urine and feces. The metabolic signature of aging consisted of changes in levels of metabolites associated with amino acid metabolism, tricarboxylic acid cycle, tryptophan–nicotinamide adenine dinucleotide pathway, and host–microbiota metabolic axis. Conclusions: Our 1H NMR-based metabolomic approach was able to characterize the effect of age on urinary and fecal metabotypes. The implementation of this analytical strategy may increase our understanding of the metabolic alterations involved in the aging process and assist in the design of anti-aging interventions. [Copyright &y& Elsevier]

Abstract: During the 2009 FINA World Aquatics Championships high-tech swimsuits were used to add buoyancy, stability, speed and endurance. The design of a material must meet several requirements. In particular, it is of crucial importance the in-depth investigation of the chemical and physical characteristics of the material itself. Data relating to the mobility of water molecules adsorbed by polymer network is a key element in view of properties in understanding the material since they are related to inter-relationship between the fluid medium and macromolecules. In the present work, the water in interaction with the polymer network of fabrics for competition swimsuit has been studied by Time Domain NMR (TD NMR) in order to better understand the molecular motions of polymer chains and solvent molecules inside the structure. Commercial materials, consisting of polyamide and elastane in different ratios, have been examined by NMR relaxometry. Results showed the presence of several types of water, each one characterized by its mobility. Using qualitative and quantitative analyses of NMR, data have been evaluated on the mechanical characteristics of the examined materials. The developed methodology in this paper is a general approach that opens up new perspectives for the study of swim wear fabric. [Copyright &y& Elsevier]

Desymmetrization of chiral α-diimines by ethyl nosyloxycarbamate using water as a co-solvent takes place with very high diastereoselectivity, the nucleophilic attack occurring only on the less hindered side of the C=N double bond. Interestingly, the presence of water in the reaction medium likely stabilizes the anion intermediate slowing down the successive cyclization reaction and favoring the rotation around the C–N single bond. In fact, as confirmed by ROESY experiments, only the two diastereomeric 3-(iminomethyl)diaziridine-1-carboxylates that differ in the absolute configuration of the alkyl substituted nitrogen atoms were always obtained in equimolar ratios. Finally, all compounds were easily obtained in optically pure form through HPLC separation and can be considered as interesting chiral synthons. [ABSTRACT FROM AUTHOR]

Abstract: Chiral racemic α-diimines, tested in aziridination reactions with NsONHCO2Et, for the first time led to the synthesis of (±)-bidiaziridines, stereoselectively derived from the corresponding meso (E-s-trans-E)-α-diimines. Moreover, a minor bidiaziridine isomer, probably a meso form that was lost under classical work-up conditions, can be obtained by adding water to the crude mixtures at the end of amination reactions. The results definitively prove that the imine aziridination by carbamates is a two-step domino process. The structures of the compounds were determined using 2D NMR on purified bidiaziridines. [Copyright &y& Elsevier]

Age-related dysbioses of intestinal microbiota and decline in the overall metabolic homeostasis are frequently found in the elderly. Probiotic supplementation may represent a way to prevent or reduce the senescence-associated metabolic disorders. The present study evaluated the metabolic impact of Lactobacillus acidophilus La5 and Bifidobacterium lactis Bb12 supplementation in relation to age by analyzing urine and feces metabolic profiles using ¹H-nuclear magnetic resonance spectroscopy and multivariate analysis. Adult (3 mo old) and aged (16 mo old) mice received an oral supplementation of the 2 probiotics (1 x 109 colony-forming units/d each) or phosphate buffered saline (control) daily for 30 d. Urine and feces were collected for 48 h before the end of the study. Partial least squares-discriminant analysis showed that the urinary discriminant metabolites for the probiotic treatment included higher dimethylglycine in adult and aged mice, lower sarcosine and nicotinate in adult mice, higher N-methylnicotinamide in adult mice and lower N-methylnicotinamide in aged mice compared with their controls. These results indicate a probiotic-induced modulation of homocysteine and NAD metabolism pathways, which have important implications because these pathways are involved in essential cellular processes that can be altered in senescence. The probiotic supplementation also modified the fecal metabolic profiles, inducing in both adult and aged mice higher 4-hydroxyphenylacetate and lower xylose in treated mice compared with their control mice, whereas valerate was greater in treated adult mice and lower in treated aged mice compared with their controls. The ANOVA simultaneous component analysis on urinary and fecal metabolic profiling showed an age x treatment interaction (P < 0.05}, confirming the age-related modulation of the metabolic response to probiotic supplementation. The results suggest that L. acidophilus and B. lactis may prevent or reduce age-related metabolic dysfunction. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study was to individuate, by bioassay-guided fractionation, promising antifungal fractions and/or constituents from Hypericum perforatum subsp. angustifolium in vitro roots. Treatments with chitosan, O-carboxymethylchitosan (CMC) and its derivatives were used to improve xanthone production in the roots. The bioassay-guided fractionation of CMC-treated roots led to the individuation of an ethyl acetate fraction, containing the highest amount of xanthones (6.8%) and showing the best antifungal activity with minimal inhibitory concentration (MIC) values of 53.82, 14.18, and 36.52 μg/ml, against Candida spp., Cryptococcus neoformans and dermatophytes, respectively. From this fraction the prenylated xanthone, biyouxanthone D has been isolated and represented the 44.59% of all xanthones detected. For the first time in the present paper biyouxanthone D has been found in H. perforatum roots and tested against C. neoformans, dermatophytes, and Candida species. The xanthone showed the greatest antifungal activity against C. neoformans and dermatophytes, with MIC values of 20.16, 22.63 μg/ml. In conclusion, the results obtained in the present study demonstrated that CMC-treated Hpa in vitro root extracts represent a tool for the obtainment of promising candidates for further pharmacological and clinical studies. [Copyright &y& Elsevier]

A challenging asymmetric reaction (aza-Michael addition of imides to enones) has been optimized through an integrated approach involving the synthesis of a family of organocatalysts, multiple catalysis (usage of additives), and finally with rational exploration of the chemical space by the application of the experiment design. [ABSTRACT FROM AUTHOR]

Abstract: The interaction of new bivalent NOP receptor antagonists with dodecyl phosphatidylcholine micelles and DMPC/cholesterol liposomes was investigated in solution by high resolution NMR. The ligands are structurally related to the NOP antagonist JTC-801 plus a propanediamine or heptanediamine spacer between the pharmacophoric units. Ligand internuclear distances were derived from 2D NOESY data and applied to molecular modelling calculations as conformational restraints. NMR experiments on micelles evidenced that the ligands closely approached the micelles but gave no hints on the preferential conformations of the interacting ligands. Results from NMR experiments in the presence of liposomes clearly indicated that both ligands strongly interacted with the bilayer assuming a preferential folded conformation with the quinoline arms superimposing on each other. The finding suggested that these strongly lipophilic pharmacophores could localize in the native receptorial membrane in the form of a depot, gaining access to the recognition site via the lipid bilayer. [ABSTRACT FROM AUTHOR]

Volatile fatty acids obtained from the fermentation of the organic fraction of municipal solid waste can be used as raw materials for non-toxic ethyl ester (EE) synthesis as well as feedstock for the production of polyhydroxyalkanoates (PHAs). Taking advantage of the concept of an integrated process of a bio-refinery, in the present paper, a systematic investigation on the extraction of intracellular poly(3-hydroxybutyrate-co-3-hydroxyvalerate), produced by mixed microbial culture by using EEs was reported. Among the tested EEs, ethyl acetate (EA) was the best solvent, dissolving the copolymer at the lowest temperature. Then, extraction experiments were carried out by EA at different temperatures on two biomass samples containing PHAs with different average molecular weights. The parallel characterization of the extracted and non-extracted PHAs evidenced that at the lower temperature (100 °C) EA solubilizes preferentially the polymer fractions richer in 3HV comonomers and with the lower molecular weight. By increasing the extraction temperature from 100 °C to 125 °C, an increase of recovery from about 50 to 80 wt% and a molecular weight reduction from 48% to 65% was observed. The results highlighted that the extracted polymer purity is always above 90 wt% and that it is possible to choose the proper extraction condition to maximize the recovery yield at the expense of polymer fractionation and degradation at high temperatures or use milder conditions to maintain the original properties of a polymer. [ABSTRACT FROM AUTHOR]

In this paper, the first phytochemical analysis of the ethanolic extract of Daphne sericea Vahl flowering aerial parts collected in Italy and its biological activities were reported. Eleven compounds were identified i.e., α-linolenic acid (1), tri-linoleoyl-sn-glycerol (2), pheophorbide a ethyl ester (3), pilloin (4), sinensetin (5), yuanhuanin (6), rutamontine (7), syringin (8), p-coumaric acid (9), p-anisic acid (10) and caffeic acid (11). To the best of our knowledge, compounds (1-4, 7-8 and 10) were isolated from D. sericea for the first time during this work, whereas sinensetin (5) represents a newly identified component of the entire Thymelaeaceae family. The extract was found to possess radical scavenging against both DPPH• and 2,2′-azino-bis(3-thylbenzothiazoline-6-sulfonic acid (ABTS•+) radicals, with at least a 40-fold higher potency against the latter. Moreover, chelating abilities against both ferrous and ferric ions have been highlighted, thus suggesting a possible indirect antioxidant power of the extract. Although the precise bioactive compounds remain to be discovered, the polyphenolic constituents, including phenolic acids, tannins and flavonoids, seem to contribute to the antioxidant power of the phytocomplex. In addition, the extract produced cytotoxic effects in MDA-MB-231 and U87-MG cancer cell lines, especially at the concentration of 625 μg/mL and after 48–72 h. Further studies are required to clarify the contribution of the identified compounds in the bioactivities of the extract and to support possible future applications. [ABSTRACT FROM AUTHOR]

Gold nanoparticles (AuNPs) are promising carriers in the field of nanomedicine and represent a very intriguing approach in drug delivery applications, due to their small size and enhanced properties. This work aims to highlight the interaction between functionalized AuNPs and the immune-system suppressant drug Methotrexate (MTX) at molecular level. Small and monodisperse (<2R H >5 ± 1 nm) gold nanoparticles were prepared by a simple chemical route using hydrophilic thiol 3-mercapto-1-propanesulfonate (3MPS) as a functionalizing/capping agent and act as a platform for post-synthesis conjugation of MTX via non-covalent interaction. The AuNPs-3MPS@MTX bioconjugate and the AuNPs alone were characterized to investigate their optical, chemical, and morphological properties. Moreover, NMR, AFM, SAXS, HR-TEM and SR-XPS data confirmed the spherical shape of AuNPs and allowed to determine the mechanisms behind such drug-nanoparticle physicochemical interactions. These analyses define the overall structure of drug-loaded AuNPs-3MPS and drug location on the colloidal nanoparticles surface. Based on the experimental data, it is notable to assert that MTX was successfully loaded on the negatively charged nanoparticles surface via electrostatic interactions. The physicochemical behavior leads to the formation of large clusters with close packed arrangement of AuNPs-3MPS@MTX. This self-assembling property is of importance for delivery purpose affecting the drug-loaded nanoparticle size, functionality, and morphology. Knowledge of how these systems behave will aid in increasing drug efficacy and in understanding the pharmacodynamics and pharmacokinetic properties, opening to new physicochemical insight for therapy and drug delivery systems. The interaction between methotrexate drug and 3-mercapto-1-propanesulfonate functionalized gold nanoparticles was studied with the aim to highlight the overall structure of drug-loaded nanoparticles. The nature of interaction can be categorized into electrostatic binding between amine groups of MTX and negatively charged thiols on gold nanoparticles surface. This interaction results in a formation of large clusters with densely packed arrangement, as demonstrated by combined SAXS, HR-TEM and SR-XPS studies. Unlabelled Image • Functionalized AuNPs loaded with Methotrexate drug. • The physicochemical interaction between AuNPs and MTX was clarified. • AFM, SAXS and HR-TEM analyses highlighted the formation of densely packed clusters. • NMR and SR-XPS data indicated an interaction via electrostatic binding. [ABSTRACT FROM AUTHOR]

The bisaziridination reaction of symmetric (E-s-trans-E)-α-diimines using ethyl nosyloxycarbamate as aminating agent yields symmetrically functionalized bidiaziridines, under mild conditions. The reactions Take place with very high stereoselectivity giving only bidiaziridines with total retention of the starting α-diimine configuration, as determined by NMR measurements. Moreover, only a single pure diastereomer, derived from attack of the obtained, starting from chiral substrates. ROESY analyses clearly show that all nitrogens have a stable pyramidal conformation, and the absolute configurations of new chiral centers were assigned. [ABSTRACT FROM AUTHOR]

The rationale inspiring the discovery of lead compounds for the treatment of human parasitic protozoan diseases from natural sources is the well-established use of medicinal plants in various systems of traditional medicine. On this basis, we decided to select an overlooked medicinal plant growing in central Italy, Marrubium incanum Desr. (Lamiaceae), which has been used as a traditional remedy against protozoan diseases, and to investigate its potential against Human African trypanosomiasis (HAT). For this purpose, we assayed three extracts of different polarities obtained from the aerial parts of M. incanum—namely, water (MarrInc-H2O), ethanol (MarrInc-EtOH) and dichloromethane (MarrInc-CH2Cl2)—against Trypanosoma brucei (TC221), with the aim to discover lead compounds for the development of antitrypanosomal drugs. Their selectivity index (SI) was determined on mammalian cells (BALB/3T3 mouse fibroblasts) as a counter-screen for toxicity. The preliminary screening selected the MarrInc-CH2Cl2 extract as the most promising candidate against HAT, showing an IC50 value of 28 μg/mL. On this basis, column chromatography coupled with the NMR spectroscopy of a MarrInc-CH2Cl2 extract led to the isolation and identification of five compounds i.e. 1-α-linolenoyl-2-palmitoyl-3-stearoyl-sn- glycerol (1), 1-linoleoyl-2-palmitoyl-3-stearoyl-sn-glycerol (2), stigmasterol (3), palmitic acid (4), and salvigenin (5). Notably, compounds 3 and 5 were tested on T. brucei, with the latter being five-fold more active than the MarrInc-CH2Cl2 extract (IC50 = 5.41 ± 0.85 and 28 ± 1.4 μg/mL, respectively). Furthermore, the SI for salvigenin was >18.5, showing a preferential effect on target cells compared with the dichloromethane extract (>3.6). Conversely, stigmasterol was found to be inactive. To complete the work, also the more polar MarrInc-EtOH extract was analyzed, giving evidence for the presence of 2″-O-allopyranosyl-cosmosiin (6), verbascoside (7), and samioside (8). Our findings shed light on the phytochemistry of this overlooked species and its antiprotozoal potential, providing evidence for the promising role of flavonoids such as salvigenin for the treatment of protozoal diseases. [ABSTRACT FROM AUTHOR]

Several epidemiological studies demonstrate that moderate (red) wine consumption may afford protection against cardiovascular diseases. Protection is ascribed to the biological activity of wine components, many of which, however, are discarded during winemaking. In vitro rat thoracic aorta rings contracted with phenylephrine or KCl were used to assess the vasorelaxant activity of extracts from wine pomaces (seeds and skins) of the Calabrian autochthonous grape variety Magliocco dolce (Arvino). NMR spectroscopy was used to ascertain their chemical composition. Data demonstrate that seed and skin, but not must, extracts are capable of relaxing vascular preparations in an endothelium-dependent manner, similarly to the red wine extract, due to the presence of comparable amounts of bioactive constituents. In rings pre-contracted with 20–30 mM KCl, only seed extracts showed a moderate relaxation. The most efficacious vasodilating extract (wine) showed a good antioxidant profile in both [(2,2-diphenyl-1-picrylhydrazyl)acid] radical (DPPH) and [2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid)] radical (ABTS) assays. In conclusion, winemaking from Magliocco dolce grape can provide potentially health-promoting by-products useful in cardiovascular disease management. [ABSTRACT FROM AUTHOR]

The execution of many genetic programs, influenced by environmental conditions, is epigenetically controlled. Thus, small molecules of the intermediate metabolism being precursors of most of nutrition-deriving epigenetic modifications, sense the cell surrounding environment. Here we describe histone H4K16 acetylation distribution in S. cerevisiae nhp6ab mutant, using ChIP-seq analysis; its transcription profile by RNA-seq and its metabolic features by studying the metabolome. We then intersected these three -omic approaches to unveil common crosspoints (if any). In the nhp6ab mutant, the glucose metabolism is switched to pathways leading to Acetyl-CoA synthesis. These enhanced pathways could lead to histone hyperacetylation altering RNA transcription, particularly of those metabolic genes that maintain high Acetyl-CoA availability. Thus, the absence of chromatin regulators like Nhp6 A and B, interferes with a regulative circular mechanism where histone modification, transcription and metabolism influence each other and contribute to clarify the more general phenomenon in which gene regulation feeds metabolic alterations on epigenetic basis. This study allowed us to identify, in these two factors, a common element of regulation in metabolism and chromatin acetylation state that could represent a powerful tool to find out relationships existing between metabolism and gene expression in more complex systems. Unlabelled Image • nhp6ab Strain shows globally hyperacetylated histones particularly at H4K16. • Metabolomic analysis shows altered glucose metabolism in the nhp6ab mutant. • Transcriptome and H4K16 acetylome are altered in the nhp6ab mutant. • NHP6A/B Affect a circuit involving histone acetylation, metabolism and transcription. [ABSTRACT FROM AUTHOR]

A graphical abstract of the article "Ethyl Nitroacetate in Aza-Henry Addition on Trifluoromethyl Aldimines: A Solvent-Free Procedure to Obtain Chiral Trifluoromethyl α,β-Diamino Esters" is presented.