Barbara Dmochowska

Vitamin C metabolomic mapping in experimental diabetes with 6-deoxy-6-fluoro-ascorbic acid and high resolution 19F-nuclear magnetic resonance spectroscopy

Metabolomic mapping is an emerging discipline geared at providing information on a large number of metabolites as a complement to genomics and proteomics. Here we have probed ascorbic acid homeostasis and degradation in diabetes using 6-deoxy-6-fluoro ascorbic acid (F-ASA) and 750 MHz (19)F-nuclear magnetic resonance (NMR) spectroscopy with proton decoupling In vitro, Cu(2+)-mediated degradation of F-ASA revealed the formation of 4 major stable degradation products at 24 hours. However, when normal or diabetics rats were injected with F-ASA intraperitoneally (IP) for 4 days, up to 20 fluorine-labeled compounds were observed in the urine. Their composition resembled, in part, metal catalyzed degradation of F-ASA and was not explained by spontaneous degradation in the urine. Diabetes led to a dramatic increase in urinary F-ASA loss and a relative decrease in most other urinary F-compounds. Diabetes tilted F-ASA homeostasis toward oxidation in liver (P <.01), kidney (P <.01), spleen (P <.01), and plasma (P <.01), but tended to decrease oxidation in brain, adrenal glands, and heart. Surprisingly, however, besides the major oxidation product fluoro-dehydroascorbic acid (F-DHA), no F-ASA advanced catabolites were detected in tissues at 5 micromol/L sensitivity. These findings not only confirm the key role of the kidney in diabetes-mediated loss of ascorbic acid, but demonstrate that only selected tissues are prone to increased oxidation in diabetes. While the structure of most degradation products needs to be established, the method illustrates the power of high resolution (19)F-NMR spectroscopy for the mapping of complex metabolomic pathways in disease states.

Mutagenicity of quaternary ammonium salts containing carbohydrate moieties

Quaternary ammonium salts are widely used in industrial, agricultural, healthcare and domestic applications. They are believed to be safe compounds, with little or no health hazard to humans. However, in this report, we demonstrate that a series of newly synthesized quaternary ammonium salts containing carbohydrate moieties reveal potent mutagenic activities, as assessed by using the Vibrio harveyi bioluminescence mutagenicity test. D-Gluco- and D-galacto-derivatives were found to have a higher mutagenic potential than D-manno-derivatives. Among the former groups of compounds, the N-[2-(D-glycopyranosyloxy)ethyl]-N,N,N-trimethylaminium salts were of the highest activity in the mutagenicity assay. These results suggest that the safety of quaternary ammonium salts may be lower than previously supposed, indicating a need for testing such compounds for their mutagenicity.

Synthesis of Some Quaternary N-(1,4-anhydro-5-deoxy-D, L-ribitol-5-yl)ammonium Salts

The successful removal of the isopropylidene-protecting group from 1,4-anhydro-2,3-O-isopropylidene-5-O-tosyl-D,L-ribitol and from quaternary N-(1,4-anhydro-5-deoxy-2,3-O-isopropylidene-D,L-ribitol-5-yl)ammonium salts is reported. The structures of all isolates were determined by spectral analysis, including extensive 2-D NMR analyses. Single-crystal x-ray diffractions of 1,4-anhydro-5-O-tosyl-D,L-ribitol and its 2,3-O-isopropylidene derivatives are reported.

DFT studies of the conversion of four mesylate esters during reaction with ammonia.

AbstractThe energetics of the Menshutkin-like reaction between four mesylate derivatives and ammonia have been computed using B3LYP functional with the 6-31+G** basis set. Additionally, MPW1K/6-31+G** level calculations were carried out to estimate activation barrier heights in the gas phase. Solvent effect corrections were computed using PCM/B3LYP/6-31+G** level. The conversion of the reactant complexes into ion pairs is accompanied by a strong energy decrease in the gas phase and in all solvents. The ion pairs are stabilized with two strong hydrogen bonds in the gas phase. The bifurcation at C2 causes a significant activation barrier increase. Also, bifurcation at C5 leads to noticeable barrier height differentiation. Both B3LYP/6-31+G** and MPW1K/6-31+G** activation barriers suggest the reaction 2 (2a + NH3) to be the fastest in the gas phase. The reaction 4 is the slowest one in all environments. FigureAmmonium salt formation in a Menshutkin-like reaction between ammonia and (S)-1,4-andydro-2,3-dideoxy-5-O-mesylpentitol (2a)

Acid-catalyzed isomerization of methyl 2-deoxy-D-arabino-hexosides: equilibria, kinetics and mechanism.

Four isomers of methyl 2-deoxy-D-arabino-hexosides were isolated by HPLC as chromatographically homogeneous compounds. The rates of pyranoside isomerization (alpha(p) and beta(p)) at 40 degrees C and of furanoside isomerization (alpha(f) and beta(f)) at 26 degrees C were determined. A mechanism has been suggested for transformations taking place during isomerization of methyl 2-deoxy-D-arabino-hexosides in methanolic solution catalyzed with hydrogen chloride.

The conformational behavior, geometry and energy parameters of Menshutkin-like reaction of O-isopropylidene-protected glycofuranoid mesylates in view of DFT calculations.

The formation of pyridinium salts in the transformation of three O-isopropylidene-protected mesylates of furanoid sugar derivatives under pyridine action is considered at the B3LYP/6-31+G** computation level. All the structures were optimized in the gas phase, in chloroform and water. Activation barrier heights in the gas phase were also estimated at the B3LYP/6-311++G**, MPW1K/6-31+G** and MPW1K/6-311++G** levels. The conducted calculations, both in the gas phase (regardless of the computation level) and in solvents, revealed the barrier height increasing order as follows: 1>2>3 for the three reactions studied. The conformational behavior of the five-membered ring is discussed in the gas phase and in solvents. The fused dioxolane ring makes the furanoid ring less likely to undergo conformational changes. In the case of reaction 3, the furanoid ring shape does not change either in the gas phase or in solvents. All conformers are close to E0 or (0)E.

Preparation, chemical and crystal structures of N-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)pyridinium chloride

Preparation and isolation of N-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-beta-D-glucopyranosyl)pyridinium chloride are described. Its structure was determined by 1H NMR spectroscopy and X-ray analysis. X-ray crystallography revealed that the salt crystallizes with one molecule of water. Ab initio calculations were used to determine charges on atoms in the cation of the title compound.

Molecular and crystal structures of N-(β-d-galactopyranosyl)pyridinium bromide and its per-O-acetylated derivative

1H NMR spectroscopy and X-ray diffraction data are described for N-(2,3,4,6-tetra-O-acetyl-beta-D-galactopyranosyl)pyridinium bromide and N-(beta-D-galactopyranosyl)pyridinium bromide. X-ray crystallography revealed that the O-acetylated salt crystallizes with two molecules of water and one molecule of ethanol.

Crystal structure of N-(tri-O-acetyl-α-d-xylopyranosyl)pyridinium bromide

Abstract The structure of N-(2,3,4-tri-O-acetyl-α- d -xylopyranosyl)pyridinium bromide was determined by X-ray crystallography and 1H NMR spectroscopy. Two xylopyranosyl moieties crystallize with three water molecules and there is a novel pattern of Br− and H2O contacts. Both xylopyranosyl rings in the asymmetric unit have the 1C4 conformation, with all three axial O-Ac groups.

Molecular dynamics study on the influence of C-terminal sugar substitution on dynamics and conformation of vancomycin derivatives

ABSTRACT Computational investigations were performed to examine the effects of the addition of 2-acetamido-2-deoxy-β-D-galactopyranosylamine or 1-amino-1-deoxy-D-glucitol connected to the C-terminus of vancomycin with different linkers. The purpose of this modification was to find more effective vancomycin derivatives by providing alternative interactions between vancomycin moiety and the peptidoglycan precursor. Each prepared vancomycin–peptidoglycan complex was optimized and submitted to the molecular dynamics study and analysis. The analysis of overall root mean square deviation, changes in position and interactions involving modified part of vancomycin as well as cluster analysis were carried out. One of the proposed vancomycin analogues seems to be efficient vancomycin substitute. GRAPHICAL ABSTRACT