Potentiometric Sensing of Nonsteroidal Painkillers by Acyclic Squaramide Ionophores.

We report here a small library of a new type of acyclic squaramide receptors (L1-L5) as selective ionophores for the detection of ketoprofen and naproxen anions (KF- and NS-, respectively) in aqueous media. 1H NMR binding studies show a high affinity of these squaramide receptors toward KF- and NS-, suggesting the formation of H-bonds between the two guests and the receptors through indole and -NH groups. Compounds L1-L5 have been tested as ionophores for the detection of KF- and NS- inside solvent PVC-based polymeric membranes. The optimal membrane compositions were established through the careful variation of the ligand/tridodecylmethylammonium chloride (TDMACl) anion-exchanger ratio. All of the tested acyclic squaramide receptors L1-L5 have high affinity toward KF- and NS- and anti-Hofmeister selectivity, with L4 and L5 showing the highest sensitivity and selectivity to NS-. The utility of the developed sensors for a high precision detection of KF- in pharmaceutical compositions with low relative errors of analysis (RSD, 0.99-1.4%) and recoveries, R%, in the range 95.1-111.8% has been demonstrated. Additionally, the chemometric approach has been involved to effectively discriminate between the structurally very similar KF- and NS-, and the possibility of detecting these analytes at concentrations as low as 0.07 µM with R2 of 0.947 and at 0.15 µM with R2 of 0.919 for NS- and KF-, respectively, was shown.

A Structural Approach to the Strength Evaluation of Linear Chalcogen Bonds.

The experimental structural features of chalcogen bonding (ChB) interactions in over 34,000 linear fragments R-Ch⋯A (Ch = S, Se, Te; R = C, N, O, S, Se, Te; A = N, O, S, Se, Te, F, Cl, Br, I) were analyzed. The bond distances dR-Ch and the interaction distances dCh⋯A were investigated, and the functions δR-Ch and δCh⋯A were introduced to compare the structural data of R-Ch⋯A fragments involving different Ch atoms. The functions δR-Ch and δCh⋯A were calculated by normalizing the differences between the relevant bond dR-Ch and ChB interaction dCh⋯A distances with respect to the sum of the relevant covalent (rcovR + rcovCh) and the van der Waals (vdW) radii (rvdWCh + rvdWA), respectively. A systematic comparison is presented, highlighting the role of the chalcogen involved, the role of the R atoms covalently bonded to the Ch, and the role of the A species playing the role of chalcogen bond acceptor. Based on the results obtained, an innovative approach is proposed for the evaluation and categorization of the ChB strength based on structural data.

Switching-On Fluorescence by Copper (II) and Basic Anions: A Case Study with a Pyrene-Functionalized Squaramide.

The new symmetric acyclic N,N'-bis(1-pyrenyl) squaramide (H2L) functionalized with the pyrene moiety as a fluorogenic fragment has been designed and its ability to selectively detect specific anions and metals investigated. H2L selectively binds Cl- both in solution (DMSO 0.5% H2O and MeCN) and in the solid state, and allows to selectively detect Cu2+ in MeCN with the formation of a 2:1 metal-receptor complex, with a green intense emission appreciable by naked eye under the UV lamp. The H2L copper complex preserves its emission properties in the presence of Cl-. The addition of basic anions (OH-, CN-, and F-) up to 10 equivalents caused the deprotonation of the squaramide NHs and a dramatic change of the emission properties of the H2L copper complex.

Dose-Dependent Effects of L-Arginine on PROP Bitterness Intensity and Latency and Characteristics of the Chemical Interaction between PROP and L-Arginine.

Genetic variation in the ability to taste the bitterness of 6-n-propylthiouracil (PROP) is a complex trait that has been used to predict food preferences and eating habits. PROP tasting is primarily controlled by polymorphisms in the TAS2R38 gene. However, a variety of factors are known to modify the phenotype. Principle among them is the salivary protein Ps-1 belonging to the basic proline-rich protein family (bPRP). Recently, we showed that oral supplementation with Ps-1 as well as its related free amino acids (L-Arg and L-Lys) enhances PROP bitterness perception, especially for PROP non-tasters who have low salivary levels of Ps-1. Here, we show that salivary L-Arg levels are higher in PROP super-tasters compared to medium tasters and non-tasters, and that oral supplementation with free L-Arg enhances PROP bitterness intensity as well as reduces bitterness latency in a dose-dependent manner, particularly in individuals with low salivary levels of both free L-Arg and Ps-1 protein. Supplementation with L-Arg also enhanced the bitterness of caffeine. We also used 1H-NMR spectroscopy and quantum-mechanical calculations carried out by Density Functional Theory (DFT) to characterize the chemical interaction between free L-Arg and the PROP molecule. Results showed that the -NH2 terminal group of the L-ArgH+ side chain interacts with the carbonyl or thiocarbonyl groups of PROP by forming two hydrogen bonds with the resulting charged adduct. The formation of this PROP•ArgH+ hydrogen-bonded adduct could enhance bitterness intensity by increasing the solubility of PROP in saliva and its availability to receptor sites. Our data suggest that L-Arg could act as a 'carrier' of various bitter molecules in saliva.

Zinc(II)-methimazole complexes: synthesis and reactivity.

The tetrahedral S-coordinated complex [Zn(MeImHS)4](ClO4)2, synthesised from the reaction of [Zn(ClO4)2] with methimazole (1-methyl-3H-imidazole-2-thione, MeImHS), reacts with triethylamine to yield the homoleptic complex [Zn(MeImS)2] (MeImS = anion methimazole). ESI-MS and MAS (13)C-NMR experiments supported MeImS acting as a (N,S)-chelating ligand. The DFT-optimised structure of [Zn(MeImS)2] is also reported and the main bond lengths compared to those of related Zn-methimazole complexes. The complex [Zn(MeImS)2] reacts under mild conditions with methyl iodide and separates the novel complex [Zn(MeImSMe)2I2] (MeImSMe = S-methylmethimazole). X-ray diffraction analysis of the complex shows a ZnI2N2 core, with the methyl thioethers uncoordinated to zinc. Conversely, the reaction of [Zn(MeImS)2] with hydroiodic acid led to the formation of the complex [Zn(MeImHS)2I2] having a ZnI2S2 core with the neutral methimazole units S-coordinating the metal centre. The Zn-coordinated methimazole can markedly modify the coordination environment when changing from its thione to thionate form and vice versa. The study of the interaction of the drug methimazole with the complex [Zn(MeIm)4](2+) (MeIm = 1-methylimidazole) - as a model for Zn-enzymes containing a N4 donor set from histidine residues - shows that methimazole displaces only one of the coordinated MeIm molecules; the formation constant of the mixed complex [Zn(MeIm)3(MeImHS)](2+) was determined.

Structure-activity relationships in cytotoxic Au(I)/Au(III) complexes derived from 2-(2'-pyridyl)benzimidazole.

Gold(I) and gold(III) complexes derived from 2-(2'-pyridyl)benzimidazole (pbiH) were proven to be a promising class of in vitro antitumor agents against A2780 human ovarian cancer cells. In this paper, a comparative electrochemical, UV-vis absorption, and emission spectroscopic investigation is reported on pbiH, the two mononuclear Au(III) complexes [(pbi)AuX2] (X = Cl (1), AcO (2)), the four mononuclear Au(I) derivatives [(pbiH)AuCl] (3), [(pbiH)Au(PPh3)]PF6 ((4(+))(PF6(-))), [(pbi)Au(PPh3)] (5), and [(pbi)Au(TPA)] (6), the three mixed-valence Au(III)/Au(I) complexes [(µ-pbi)Au2Cl3] (7), [(Ph3P)Au(µ-pbi)AuX2]PF6 (X = Cl ((8(+))(PF6(-))), AcO ((9(+))(PF6(-)))), and the binuclear Au(I)-Au(I) compound [(µ-pbi)Au2(PPh3)2]PF6 ((10(+))(PF6(-))). All complexes feature irreversible reduction processes related to the Au(III)/Au(I) or Au(I)/Au(0) processes and peculiar luminescent emission at about 360-370 nm in CH2Cl2, with quantum yields that are remarkably lower ((0.7-14.5) × 10(-2)) in comparison to that determined for the free pbiH ligand (31.5 × 10(-2)) in the same solvent. The spectroscopic and electrochemical properties of all complexes were interpreted on the grounds of time-dependent PBE0/DFT calculations carried out both in the gas phase and in CH2Cl2 implicitly considered within the IEF-PCM SCRF approach. The electronic structure of the complexes, and in particular the energy and composition of the Kohn-Sham LUMOs, can be related to the antiproliferative properties against the A2780 ovarian carcinoma cell line, providing sound quantitative structure-activity relationships and shedding a light on the role played by the global charge and nature of ancillary ligands in the effectiveness of Au-based antitumor drugs.

Marked increase in PROP taste responsiveness following oral supplementation with selected salivary proteins or their related free amino acids.

The genetic predisposition to taste 6-n-propylthiouracil (PROP) varies among individuals and is associated with salivary levels of Ps-1 and II-2 peptides, belonging to the basic proline-rich protein family (bPRP). We evaluated the role of these proteins and free amino acids that selectively interact with the PROP molecule, in modulating bitter taste responsiveness. Subjects were classified by their PROP taster status based on ratings of perceived taste intensity for PROP and NaCl solutions. Quantitative and qualitative determinations of Ps-1 and II-2 proteins in unstimulated saliva were performed by HPLC-ESI-MS analysis. Subjects rated PROP bitterness after supplementation with Ps-1 and II-2, and two amino acids (L-Arg and L-Lys) whose interaction with PROP was demonstrated by (1)H-NMR spectroscopy. ANOVA showed that salivary levels of II-2 and Ps-1 proteins were higher in unstimulated saliva of PROP super-tasters and medium tasters than in non-tasters. Supplementation of Ps-1 protein in individuals lacking it in saliva enhanced their PROP bitter taste responsiveness, and this effect was specific to the non-taster group.(1)H-NMR results showed that the interaction between PROP and L-Arg is stronger than that involving L-Lys, and taste experiments confirmed that oral supplementation with these two amino acids increased PROP bitterness intensity, more for L-Arg than for L-Lys. These data suggest that Ps-1 protein facilitates PROP bitter taste perception and identifies a role for free L-Arg and L-Lys in PROP tasting.