Thiourea Derivative of 2-[(1 R)-1-Aminoethyl]phenol: A Flexible Pocket-like Chiral Solvating Agent (CSA) for the Enantiodifferentiation of Amino Acid Derivatives by NMR Spectroscopy

Thiourea derivatives of 2-[(1R)-1-aminoethyl]phenol, (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol, (1R,2R)-(1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol, and (R)-1-phenylethanamine have been compared as chiral solvating agents (CSAs) for the enantiodiscrimination of derivatized amino acids using nuclear magnetic resonance (NMR) spectroscopy. Thiourea derivative, prepared by reacting 2-[(1R)-1-aminoethyl]phenol with benzoyl isothiocyanate, constitutes an effective CSA for the enantiodiscrimination of N-3,5-dinitrobenzoyl (DNB) derivatives of amino acids with free or derivatized carboxyl functions. A base additive 1,4-diazabicyclo[2.2.2]octane(DABCO)/N,N-dimethylpyridin-4-amine (DMAP)/NBu4OH) is required both to solubilize amino acid derivatives with free carboxyl groups in CDCl3 and to mediate their interaction with the chiral auxiliary to attain efficient differentiation of the NMR signals of enantiomeric substrates. For ternary systems CSA/substrate/DABCO, the chiral discrimination mechanism has been ascertained through the NMR determination of complexation stoichiometry, association constants, and stereochemical features of the diastereomeric solvates

Renewable Resources for Enantiodiscrimination: Chiral Solvating Agents for NMR Spectroscopy from Isomannide and Isosorbide

A new family of chiral selectors was synthesized in a single synthetic step with yields up to 84% starting from isomannide and isosorbide. Mono- or disubstituted carbamate derivatives were obtained by reacting the isohexides with electron-donating arylisocyanate (3,5-dimethylphenyl- or 3,5-dimethoxyphenyl-) and electron-withdrawing arylisocyanate (3,5-bis(trifluoromethyl)phenyl-) groups to test opposite electronic effects on enantiodifferentiation. Deeper chiral pockets and derivatives with more acidic protons were obtained by derivatization with 1-naphthylisocyanate and p-toluenesulfonylisocyanate, respectively. All compounds were tested as chiral solvating agents (CSAs) in H-1 NMR experiments with rac-N-3,5-dinitrobenzoylphenylglycine methyl ester in order to determine the influence of different structural features on the enantiodiscrimination capabilities. Some selected compounds were tested with other racemic analytes, still leading to enantiodiscrimination. The enantiodiscrimination conditions were then optimized for the best CSA/analyte couple. Finally, a 2D- and 1D-NMR study was performed employing the best performing CSA with the two enantiomers of the selected analyte, aiming to determine the enantiodiscrimination mechanism, the stoichiometry of interaction, and the complexation constant

2-Methyl-β-cyclodextrin grafted ammonium chitosan: synergistic effects of cyclodextrin host and polymer backbone in the interaction with amphiphilic prednisolone phosphate salt as revealed by NMR spectroscopy

Reduced molecular weight chitosan was quaternized with 2-chloro-N,N-diethylethylamine to obtain a water soluble derivative (N+-rCh). Methylated-β-cyclodextrin (MCD), with 0.5 molar substitution, was covalently linked to N+-rCh through 1,6-hexamethylene diisocyanate spacer to give the derivatized ammonium chitosan N+-rCh-MCD. To shed light on the role of the cyclodextrin pendant in guiding binding interactions with amphiphilic active ingredients, corticosteroid prednisolone phosphate salt (PN) was considered. The deep inclusion of PN into cyclodextrin in PN/MCD model system was pointed out by analysis of 1H NMR complexation shifts, 1D ROESY spectra, and diffusion measurements (DOSY). By using proton selective relaxation rates measurements as investigation tool, the superior affinity of N+-rCh-MCD towards PN was demonstrated in comparison with parent ammonium chitosan N+-rCh

Rilevazione statistica della diffusione e della conoscenza di sostanze dopanti, integratori e dell' Exercise Addiction

I benefici derivanti dalla pratica dell'esercizio fisico sono stati ampiamente documentati. Tuttavia, l’eccessivo ricorso alla attività fisica può condurre alla messa in atto di pattern compulsivi di allenamento che possono evolversi in una vera e propria patologia: l' exercise addiction. Studi recenti suggeriscono l'espansione di due fenomeni: il doping amatoriale e l'abuso di integratori per lo sport. Sono stati somministrati 686 test. I partecipanti allo studio sono stati scelti tra studenti di scuola media superiore, studenti universitari e frequentatori di ambienti sportivi. Il 42,5% degli intervistati dichiara di assumere sostanze per migliorare le prestazioni sportive e quindi di doparsi. Il 30,23% assume integratori. Una percentuale compresa tra il 35 e l'88,35 % dichiara di non conoscere le sostanze proposte.Il 15,8% dei rispondenti è a “rischio” di exercise addiction, il 71,7% è classificato come “sintomatico”. E' stata infine indagata quale possibile correlazione potesse esserci tra le variabili in esame. La statistica test X2 evidenzia che non vi è alcuna associazione , in altre parole non sembra esserci relazione tra il rischio di dipendenza dall' esercizio fisico e l'assunzione di sostanze. L'analisi dei dati raccolti suggerisce invece che vi sia un'espansione del fenomeno del doping in ambiente amatoriale e che vi sia una scriteriata e incongrua assunzione di integratori per lo sport. La presente ricerca suggerisce che occorre compiere interventi immediati sia a livello di informazione che di prevenzione , in cui al farmacista sia affidato un ruolo di primo piano

Methylammonium-formamidinium reactivity in aged organometal halide perovskite inks

Over the past 10 years, organometal halide perovskites have revolutionized the field of optoelectronics, particularly of emerging photovoltaic technologies. Today's best perovskite solar cells use triple-cation compositions containing a mixture of formamidinium, methylammonium, and cesium to enable more reproducible and stable device performance. The common procedure uses as-prepared precursor ink to avoid an undesirable decrease in device performance, attributed recently to a chemical reaction between methylammonium and formamidinium in solution. Here we employ nuclear magnetic resonance spectroscopy to explore different experimental conditions that can significantly modify these reaction kinetics; in particular, we find that the presence of cesium as the third cation can substantially slow down methylammonium-formamidinium reactivity. Our findings allow us to draw up a protocol for extended overtime perovskite ink stabilization

Carba-D,L-allal- and -D,L-galactal-derived vinyl N-nosyl aziridines as useful tools for the synthesis of 4-deoxy-4-(N-nosylamino)-2,3-unsaturated-5a-carbasugars

The novel carba-D,L-allal- and carba-D,L-galactal-derived vinyl N-nosyl aziridines were prepared and the regio- and stereoselective behavior in opening reactions with O- and N-nucleophiles examined. The carbaglycosylating ability of the novel aziridines, as deduced by the amount of 1,4-addition products (1,4-regioselectivity) obtained in the acid-catalyzed methanolysis taken as a model reaction, is similar or superior to that observed with the corresponding carba-D,L-allal- and -D,L-galactal-derived vinyl epoxides, respectively. In all 1,2- and 1,4-addition products obtained, a –(N-nosylamino) group is regio- and stereoselectively introduced at the C(4) carbon of a 1,2- or 2,3-unsaturated carbasugar, susceptible to further elaborations toward aminocyclitol derivatives. The stereoselective synthesis of the corresponding, enantiomerically pure carba-D,L-allal- and -D,L-galactal-derived vinyl N-acetyl aziridines is also described

Thiolated 2-Methyl-β-Cyclodextrin as a Mucoadhesive Excipient for Poorly Soluble Drugs: Synthesis and Characterization

Thiolated cyclodextrins are structurally simple mucoadhesive macromolecules, which are able to host drugs and increase their apparent water solubility, as well as interact with the mucus layer prolonging drug residence time on the site of absorption. The aim of this study was to synthesize through green microwave-assisted process a freely soluble thiolated 2-methyl-β-cyclodextrin (MβCD-SH). Its inclusion complex properties with dexamethasone (Dex), a poor water soluble drug, and mucoadhesive characteristics were also determined. The product was deeply characterized through NMR spectroscopy (2D COSY, 2D HSQC, 1D/2D TOCSY, and 1D ROESY), showing a thiolation degree of 67%, a selective thiolation on the C6 residues and a monomeric structure. The association constant of MβCD and MβCD-SH with Dex resulted in 2514.3 ± 32.3 M−1 and 2147.0 ± 69.3 M−1, respectively, indicating that both CDs were able to host the drug. Microrheological analysis of mucin in the presence of MBCD-SH showed an increase of complex viscosity, G′ and G′′, due to disulphide bond formation. The cytotoxicity screening on fibroblast BALB/3T3 clone A31 cells indicated an IC50 of 27.7 mg/mL and 30.0 mg/mL, for MβCD and MβCD-SH, respectively. Finally, MβCD-SH was able to self-assemble in water into nanometric structures, both in the presence and absence of the complexed drug

Deuterium retention and erosion in liquid Sn samples exposed to D2 and Ar plasmas in GyM device

The use of tin (Sn) as a liquid metal for plasma facing components has been recently proposed as a solution to the high heat load issue on the divertor target plates in nuclear fusion reactors. Due to its low vapor pressure, low reactivity with hydrogen and good resilience to neutron impact, tin is a good candidate as plasma facing component. However its high atomic number poses concerns about plasma contamination.In this paper two fundamental aspects have been investigated: deuterium retention and erosion fluxes from the Sn surface towards the plasma. The samples were exposed to plasma inside the linear machine GyM in magnetic cusp configuration. This setup permits to expose free liquid specimens without the need for the Capillary Porous System. Moreover it permits to lower the magnetic field in order to increase Sn Larmor radius and consequently limit Sn re-deposition in erosion experiments.Ex-situ analyses by ion beam diagnostics on solid samples exposed to deuterium plasma have proved that the amount of retained atomic deuterium is very low, approximately 0.18 at% estimated by Nuclear Reaction Analysis and 0.25 at% estimated by Elastic Recoil Detection Analysis.In the framework of erosion studies, the spectroscopic parameter S/XB was evaluated in Ar plasma for the SnI line at 380.1 nm by Optical Emission Spectroscopy and mass loss measurements in the 5–11 eV Te range, at a density ne ∼ 1.5 × 1011 cm−3. An average value of 150 ± 23 was obtained. Keywords: Liquid metals, Deuterium retention, Erosion, Double-cusp magnetic configuration, Ion beam diagnostics, S/XB spectroscopic paramete

Gli1/DNA interaction is a druggable target for Hedgehog-dependent tumors

Hedgehog signaling is essential for tissue development and stemness, and its deregulation has been observed in many tumors. Aberrant activation of Hedgehog signaling is the result of genetic mutations of pathway components or other Smo-dependent or independent mechanisms, all triggering the downstream effector Gli1. For this reason, understanding the poorly elucidated mechanism of Gli1-mediated transcription allows to identify novel molecules blocking the pathway at a downstream level, representing a critical goal in tumor biology. Here, we clarify the structural requirements of the pathway effector Gli1 for binding to DNA and identify Glabrescione B as the first small molecule binding to Gli1 zinc finger and impairing Gli1 activity by interfering with its interaction with DNA. Remarkably, as a consequence of its robust inhibitory effect on Gli1 activity, Glabrescione B inhibited the growth of Hedgehog-dependent tumor cells in vitro and in vivo as well as the self-renewal ability and clonogenicity of tumor-derived stem cells. The identification of the structural requirements of Gli1/DNA interaction highlights their relevance for pharmacologic interference of Gli signaling