ABSTRACT
The reactions of 2,4-bis(4-methoxyphenyl)-1,3-dithio-2,4-diphosphetane-2,4-disulfide (Lawesson's Reagent, LR) with benzylamine (BzNH2) and 4-phenylbutylamine (PhBuNH2) yield benzylammonium P-(4-methoxyphenyl)-N-benzyl-amidodithiophosphonate (BzNH3)(BzNH-adtp) and 4-phenylbutylammonium P-(4-methoxyphenyl)-N-(4-phenylbutyl)-amidodithiophosphonate (PhBuNH3)(PhBuNH-adtp). The relevant nickel complexes [Ni(BzNH-adtp)2] and [Ni(PhBuNH-adtp)2] and the corresponding hydrolysed derivatives (BzNH3)2[Ni(dtp)2] and (PhBuNH3)2[Ni(dtp)2] were prepared and fully characterized. The antimicrobial activity of the aforementioned amidodithiophosphonates against a set of Gram-positive and Gram-negative pathogen bacteria was evaluated, and [Ni(BzNH-adtp)2] and [Ni(PhBuNH-adtp)2] showed antiproliferative activity towards Staphylococcus aureus and Staphylococcus haemolyticus strains. density functional theory (DFT) calculations were performed to shed some light on the activity of reported compounds related to their tendency towards P-N bond cleavage.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Chemistry, Pharmaceutical/methods , Microbial Sensitivity Tests , Nickel/chemistry , Biofilms/drug effects , Candida/drug effects , Coordination Complexes/chemistry , Drug Design , Escherichia/drug effects , Hydrolysis , Ligands , Models, Molecular , Nitrogen/chemistry , Phosphorus/chemistry , Pseudomonas/drug effects , Quantum Theory , Spectroscopy, Fourier Transform Infrared , Staphylococcus aureus/drug effects , Staphylococcus haemolyticus/drug effects , X-Ray DiffractionABSTRACT
Oral sensitivity to fats varies in individuals influencing nutritional status and health. Variations in oleic acid perception are associated with CD36 and odorant binding protein (OBPIIa) polymorphisms, and 6-n-propylthiouracil (PROP) sensitivity, which is mediated by TAS2R38 receptor. L-Arginine (L-Arg) supplementation was shown to modify the perception of the five taste qualities. Here we analyzed the effect of three concentrations (5, 10, 15 mmol/L) of L-Arg on oral perception of oleic acid in forty-six subjects classified for PROP taster status and genotyped for TAS2R38, CD36 and OBPIIa polymorphisms. L-Arg supplementation was effective in increasing the perceived intensity of oleic acid in most subjects. The lowest concentration was the most effective, especially in PROP non-tasters or medium tasters, and in subjects with at least an allele A in CD36 and OBPIIa loci. Density Functional Theory (DFT) calculations were exploited to characterize the chemical interaction between L-Arg and oleic acid, showing that a stable 1:1 oleate·ArgH+ adduct can be formed, stabilized by a pair of hydrogen bonds. Results indicate that L-Arg, acting as a 'carrier' of fatty acids in saliva, can selectively modify taste response, and suggest that it may to be used in personalized dietetic strategies to optimize eating behaviors and health.
Subject(s)
Arginine/pharmacology , CD36 Antigens/genetics , Lipocalins/genetics , Oleic Acid/pharmacology , Polymorphism, Single Nucleotide , Propylthiouracil/pharmacology , Taste Perception/genetics , Taste/drug effects , Adult , Drug Interactions , Female , Humans , Male , Quantitative Trait Loci/genetics , Receptors, G-Protein-Coupled/genetics , Taste Buds/metabolism , Taste Perception/drug effects , Young AdultABSTRACT
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 PROPâ¢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.
Subject(s)
Arginine/pharmacology , Propylthiouracil/chemistry , Saliva/chemistry , Taste Perception/drug effects , Taste/drug effects , Adult , Arginine/administration & dosage , Caffeine/chemistry , Carbonic Anhydrases/genetics , Carbonic Anhydrases/physiology , Dose-Response Relationship, Drug , Female , Food Preferences/drug effects , Genotype , Humans , Hydrogen Bonding , Magnetic Resonance Spectroscopy , Male , Phenotype , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/physiology , Solubility , Taste/physiology , Taste Perception/genetics , Taste Perception/physiology , Young AdultABSTRACT
Attention is devoted to the role of chelating agents in the treatment of aluminium related diseases. In fact, in spite of the efforts that have drastically reduced the occurrence of aluminium dialysis diseases, they so far constitute a cause of great medical concern. The use of chelating agents for iron and aluminium in different clinical applications has found increasing attention in the last thirty years. With the aim of designing new chelators, we synthesized a series of kojic acid derivatives containing two kojic units joined by different linkers. A huge advantage of these molecules is that they are cheap and easy to produce. Previous works on complex formation equilibria of a first group of these ligands with iron and aluminium highlighted extremely good pMe values and gave evidence of the ability to scavenge iron from inside cells. On these bases a second set of bis-kojic ligands, whose linkers between the kojic chelating moieties are differentiated both in terms of type and size, has been designed, synthesized and characterized. The aluminium(III) complex formation equilibria studied by potentiometry, electrospray ionization mass spectroscopy (ESI-MS), quantum-mechanical calculations and (1)H NMR spectroscopy are here described and discussed, and the structural characterization of one of these new ligands is presented. The in vivo studies show that these new bis-kojic derivatives induce faster clearance from main organs as compared with the monomeric analog.
Subject(s)
Aluminum/chemistry , Chelating Agents/chemistry , Chelating Agents/pharmacology , Animals , Chelating Agents/chemical synthesis , Chelating Agents/pharmacokinetics , Chemistry Techniques, Synthetic , Female , Gallium Radioisotopes/pharmacokinetics , Ligands , Magnetic Resonance Spectroscopy , Mice , Molecular Structure , Pyrones/chemistry , Spectrometry, Mass, Electrospray Ionization , Tissue DistributionABSTRACT
New organoselenium(II) halides of the type [RSe](+)X(-) [R = 2,6-(Me2NCH2)2C6H3; X = Cl (2), Br (3), I (4)] were prepared by cleavage of the Se-Se bond in R2Se2 (1) with SO2Cl2 followed by halogen exchange when organoselenium chloride was treated with NaBr or KI. The reaction between 2 and R'2MCln resulted in new ionic [RSe](+)[R'2MCl(n+1)](-) [R' = 2-(Me2NCH2)C6H4, n = 1, M = Sb (5), Bi (6); R' = Ph, M = Sb, n = 1 (7) or n = 3 (8)] species. All new compounds were investigated in solution by multinuclear NMR spectroscopy ((1)H, (13)C, (77)Se, 2D experiments) and mass spectrometry. The ionic nature of 2 and the antimonates species was confirmed by conductivity studies. The molecular structures of [{2,6-(Me2NCH2)2C6H3}Se](+)Cl(-)·nH2O (2·H2O and 2·2H2O) and [{2,6-(Me2NCH2)2C6H3}Se](+)[Ph2SbCl4](-) (8), respectively, were established by single-crystal X-ray diffraction, pointing out that the ionic nature of these compounds is also preserved in the solid state, with both nitrogen atoms strongly trans coordinated to the selenium atom of the cation. Theoretical calculations carried out at the DFT level were exploited to investigate the nature of the bonding in compounds 2-4 and the free cation [RSe](+) (2a). A topological analysis based on the theory of Atoms-In-Molecules (AIM) and Electron Localization Function (ELF) jointly to a Natural Bond Orbital (NBO) approach was used to shed light on the effect of the nature of the halogen species X on the bonding within the 3c-4e N-Se-N moiety.
Subject(s)
Halogens/chemistry , Organometallic Compounds/chemistry , Quantum Theory , Selenium/chemistry , Ligands , Models, Chemical , Molecular Structure , Organometallic Compounds/chemical synthesisABSTRACT
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.