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

Nuclear proliferation and the stability-instability paradox

This thesis tests the theory that nuclear proliferation might enhance strategic stability by making the use of military force between possessors of nuclear weapons unlikely. It discusses the existing literature on deterrence and nonproliferation, emphasizing the stability-instability paradox. The stability- instability paradox offers an alternative to the optimism of deterrence logic, which views nuclear weapons as a beneficial and stabilizing force, and the pessimism of nonproliferation, which foresees dire consequences in the spread of nuclear weapons. The paradox is a synthesis of deterrence and nonproliferation logic because it allows for the coexistence of nuclear peace and lower levels of conventional war. Three cases of nuclear rivalry are examined. They are the United States and the Soviet Union, the Soviet Union and the People's Republic of China, and India and Pakistan. These cases provide evidence that challenges the Waltzian argument that nuclear weapons enhance international stability by forbidding violent response to confrontations between nuclear-armed states. Nuclear powers that have employable conventional forces at their disposal, a territorial interest at stake, and exist in a condition of nuclear stalemate can, and do, engage in conventional warfare.http://archive.org/details/nuclearprolifera1094531401NANAU.S. Navy (U.S.N.) author

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

Analytical Solutions of Viscoelastic Nonlocal Timoshenko Beams

A consistent nonlocal viscoelastic beam model is proposed in this paper. Specifically, a Timoshenko bending problem, where size-and time-dependent effects cannot be neglected, is investigated. In order to inspect scale phenomena, a stress-driven nonlocal formulation is used, whereas to simulate time-dependent effects, fractional linear viscoelasticity is considered. These two approaches are adopted to develop a new Timoshenko bending model. Analytical solutions and application samples of the proposed formulation are presented. Moreover, in order to show influences of viscoelastic and size effects on mechanical response, parametric analyses are provided. The contributed results can be useful for the design and optimization of small-scale devices exhibiting flexural behaviour

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

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

Microenvironment and tumor inflammatory features improve prognostic prediction in gastro-entero-pancreatic neuroendocrine neoplasms

Microenvironment-related immune and inflammatory markers, when combined with established Ki-67 and morphology parameters, can improve prognostic prediction in gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs). Therefore, we evaluated the prognostic value of microenvironment and tumor inflammatory features (MoTIFs) in GEP-NENs. For this purpose, formalin-fixed paraffin-embedded tissue sections from 350 patients were profiled by immunohistochemistry for immune, inflammatory, angiogenesis, proliferation, NEN-, and fibroblast-related markers. A total of 314 patients were used to generate overall survival (OS) and disease-free survival (DFS) MoTIFs prognostic indices (PIs). PIs and additional variables were assessed using Cox models to generate nomograms for predicting 5-year OS and DFS. A total of 36 patients were used for external validation of PIs and nomograms' prognostic segregations. From our analysis, G1/G2 versus G3 GEP-NENs showed phenotypic divergence with immune-inflammatory markers. HLA, CD3, CD8, and PD-1/PD-L1 IHC expression separated G3 into two sub-categories with high versus low adaptive immunity-related features. MoTIFs PI for OS based on COX-2Tumor(T) > 4, PD-1Stromal(S) > 0, CD8S < 1, and HLA-IS < 1 was associated with worst survival (hazard ratio [HR] 2.50; 95% confidence interval [CI], 2.12–2.96; p < 0.0001). MoTIFs PI for DFS was based on COX-2T > 4, PD-1S > 4, HLA-IS < 1, HLA-IT < 2, HLA-DRS < 6 (HR 1.77; 95% CI, 1.58–1.99; p < 0.0001). Two nomograms were developed including morphology (HR 4.83; 95% CI, 2.30–10.15; p < 0.001) and Ki-67 (HR 11.32; 95% CI, 5.28–24.24; p < 0.001) for OS, and morphology (PI = 0: HR 10.23; 95% CI, 5.67–18.47; PI = 5: HR 2.87; 95% CI, 1.21–6.81; p < 0.001) and MoTIFs PI for DFS in well-differentiated GEP-NENs (HR 6.21; 95% CI, 2.52–13.31; p < 0.001). We conclude that G1/G2 to G3 transition is associated with immune-inflammatory profile changes; in fact, MoTIFs combined with morphology and Ki-67 improve 5-year DFS prediction in GEP-NENs. The immune context of a subset of G3 poorly differentiated tumors is consistent with activation of adaptive immunity, suggesting a potential for responsiveness to immunotherapy targeting immune checkpoints

Efficient Ligand Passivation Enables Ultrastable CsPbX3 Perovskite Nanocrystals in Fully Alcohol Environments

Halide perovskite nanocrystals (PNCs) have demonstrated their wide potential to fabricate efficient optoelectronic devices and to prepare promising photocatalysts for solar-driven photo(electro)chemical reactions. However, their use in most of the practical applications is limited due to the instability of PNCs in polar environments. Here, the preparation of non-encapsulated CsPbX3 nanocrystals dispersed in fully alcohol environments, with outstanding stability through surface defect passivation strategy is reported. By using didodecyldimethylammonium bromide (DDAB) during material post-treatment, highly luminescent CsPbBr3 PNCs with remarkable stability in methanol/butanol medium up to 7 months with near-unity photoluminescence quantum yield are achieved. This approach is extrapolated to stabilize iodine-based CsPbBr3-xIx and CsPbI3 PNCs, showing an improvement of their photoluminescence features and stability in these high polar alcohols up to 6 h. DDAB mediates the defect suppression through ligand exchange and avoids the full permeation of alcohol to be in contact with the PNCs. In this context, DDAB induces ionization of alcohol molecules to strengthen the surface passivation. The findings open the door to the development of long-term stable CsPbX3 PNCs with high optical performance to be used in polar environments.This work was supported by the European Innovation Council (EIC) via OHPERA project (grant agreement 101071010), the Spanish Ministry of Science and Innovation under projects STABLE (PID2019-107314RB-I00) and ECOCAT (PID2020-116093RB-C41), the Spanish Ministry of Science and Innovation under project She-LED (PID2021-122960OA-I00), and the Generalitat Valenciana via Prometeo Grant Q-Solutions (CIPROM/2021/078). C.A.M. acknowledges APOSTD grant (APOSTD/2021/251) for funding. The authors also thank the Ministry of Education, Youth and Sports of the Czech Republic for the financial support of XPS measurements using CEMNAT infrastructure (project LM 2018103). The authors are very grateful to the “Serveis Centrals d'Instrumentació Científica (SCIC)” of the Universitat Jaume I