Definitive identification of cysteine and glutathione complexes of bismuth by mass spectrometry: assessing the biochemical fate of bismuth pharmaceutical agents

Solutions containing BiCl3, bismuth subsalicylate or Bi(NO3)3 with L-cysteine, DL-homocysteine, D-methionine or glutathione have been examined by electrospray mass spectrometry. Prominent peaks are assigned to bismuth complexes of these biomolecules and provide insight towards understanding the bioactivity of bismuth compounds.     

A structural and energetics analysis of the binding of a series of N-acetylneuraminic-acid-based inhibitors to influenza virus sialidase

Summary A molecular dynamics/energy-minimisation protocol has been used to analyse the structural and energetic effects of functional group substitution on the binding of a series of C4-modified 2-deoxy-2,3-didehydro-N-acetylneuraminic acid inhibitors to influenza virus sialidase. Based on the crystal structure of sialidase, a conformational searching protocol, incorporating multiple randomisation steps in a molecular dynamics simulation was used to generate a range of minimum-energy structures. The calculations were useful for predicting the number, location, and orientation of structural water molecules within protein-ligand complexes. Relative binding energies were calculated for the series of complexes using several empirical molecular modelling approaches. Energies were computed using molecular-mechanics-derived interactions as the sum of pairwise atomic nonbonded energies, and in a more rigorous manner including solvation effects as the change in total electrostatic energy of complexation, using a continuum-electrostatics (CE) approach. The CE approach exhibited the superior correlation with observed affinities. Both methods showed definite trends in observed and calculated binding affinities; in both cases inhibitors with a positively charged C4 substituent formed the tightest binding to the enzyme, as observed experimentally.This paper is based on a presentation given at the 14th Molecular Graphics and Modelling Society Conference, held in Cairns, Australia, August 27–September 1, 1995.Presently on a visiting postdoctoral fellowship in the Department of Biomolecular Structure, Glaxo Research & Development Ltd, Greenford, Middlesex UB6 OHE, U.K.     

Reactions of Charged Substrates. 4. The Gas-Phase Dissociation of (4-Substituted benzyl)dimethylsulfoniums and -pyridiniums

The relative rates for the gas-phase dissociation RX(+) --> R(+) + X degrees of five (4-Y-substituted benzyl)dimethysulfoniums (Y = MeO, Me, H, Cl, and NO(2)) and 24 (4-Y-substituted benzyl)-3'-Z-pyridiniums (complete series for Z = CN, Cl, CONH(2), and H, and 4-methoxy- and 4-nitrobenzyls for Z = F and CH(3)CO) were measured using liquid secondary ion mass spectrometry. The Hammett plot (vs deltaDeltaG degrees or sigma(+)) is linear for the sulfoniums, but plots for the four pyridinium series have a drastic break between the 4-Cl and 4-NO(2) substrates. Br?nsted-like plots for the pyridiniums show a strong leaving group effect only for 4-nitrobenzyls. An analysis of these linear free energy relations with supporting evidence from semiempirical computations suggests that collisionally activated pyridinium substrates dissociate by two pathways, direct dissociation and through an ion-neutral complex intermediate. Comparison of these results with results for the solution reactions of some of these compounds shows that the mechanism is different in the gas and solution phases. Sufficient experimental data are not available to assign a mechanism for dissociation to the sulfonium series, but computational results show characteristics of a direct dissociative mechanism.     

Low-Field NMR Relaxation Analysis of High-Pressure Ethane Adsorption in Mesoporous Silicas

Understanding the behaviour of short-chain hydrocarbons confined to porous solids informs the targeted extraction of natural resources from geological features, and underpins rational developments in separation, storage and catalytic conversion processes. Herein, we report the application of low-field (12.7 MHz) ¹H nuclear magnetic resonance (NMR) relaxation measurements to characterise ethane dynamics within mesoporous silica materials exhibiting mean pore diameters between 6 and 50 nm. Our measurements provide NMR-based adsorption isotherms within the range 25–50 bar and at ambient temperature, incorporating the ethane condensation point (40.7 bar at our experimental temperature of 23.6 °C). The quantitative nature of the acquired data is validated via a direct comparison of NMR-derived excess adsorption capacities with ex situ gravimetric ethane adsorption measurements, which are demonstrated to agree to within 0.2 mmol g⁻¹ of the observed ethane capacity. NMR relaxation time distributions are further demonstrated as a means to decouple interparticle and mesopore dominated adsorption phenomena, with unexpectedly rapid relaxation rates associated with interparticle ethane gas confirmed via a direct comparison with NMR self-diffusion analysis.     

Oxidative addition of dialkylphosphites to complexes of iridium(I) and rhodium(I)

The PH bond of dialkylphosphites (dimethylphosphite, 5,5-dimethyl-1,3-dioxa-2-phosphorinane and 4,4,5,5-tetramethyl-1,3-dioxa-2-phospholane) oxidatively adds to irClL₂(L = PPh₃, AsPh₃) and IrCl(PMe₂Ph)₃ generated in situ to give six-coordinate hydrido(dialkylphosphonato)iridium(III) complexes, e.g. IrHClL₂[{(MeO)₂-PO}₂H] and IrHCl(PMe₂Ph)₃[PO(OMe)₂]. Addition of triphenylphosphine to a solution containing [IrCl(C₈H₁₄)₂]₂ and dimethylphosphite in a 1:2 mol ratio gives a five-coordinate hydrido (dimethylphosphonato)iridium(III) complex IrHCl(PPh₃)₂{PO(OMe)₂}, from which six-coordinate pyridine and acetylacetonato complexes IrHCl(PPh₃)₂(C₅H₅N){PO(OMe)₂} and IrH(PPh₃)₂(acac){PO(OMe)₂} can be obtained. The ligand arrangements in the various complexes are inferred from IR, ¹H and ³¹P NMR data.     

Siloxane-containing polyenaminoesters

Polyenaminoesters were prepared by condensation of succinyl succinic ester (SSE) and p-bis-carbomethoxy diacetyl benzene (CDB) with 1,3-bis(3-aminopropyl)-1,1,3,3-tetramethyldisiloxane. Conditions of solvent and temperature were discovered which yielded soluble polymer from SSE after heat treatment. CDB yields only tough, rubbery, insoluble products.     

Asymmetric [2,3]-rearrangement of glycine-derived allyl ammonium ylids

The first examples of highly enantioselective [2,3]-sigmatropic rearrangements of acyclic allylic ammonium ylids are reported. Thus, a range of N-{2'-[(N'-allyl-N',N'-dialkyl)ammonium]}acetyl camphor sultams undergo rearrangement at 0 degrees C in DME solution with high diastereofacial control (up to 99:1 dr) to give allylglycines in generally high yield. The power of the method has been demonstrated in a rapid and efficient synthesis of (R)-allyl glycine.     

Gas chromatographic-electron-impact mass fragmentometric determination of lysergic acid diethylamide in urine

A sensitive method for the detection and quantitation of lysergic acid diethylamide (LSD) in urine was developed. After initial solvent extraction, the compound was further purified by liquid-liquid extraction or by solid-phase extraction. The trimethylsilyl derivative of LSD was detected by gas chromatography-mass spectrometry (GC-MS) operated in the electron-impact mode with selected-ion monitoring. The presence of LSD was confirmed by comparing retention times and relative abundances of ions of unknowns with that of a standard. The recovery of this procedure was greater than 89%. The intra-run and inter-run coefficients of variation were less than 5% and less than 7%, respectively. This procedure allows detection of LSD concentrations as low as 29 pg/ml. Quantitation of LSD was linear over the concentration range 50-2000 pg/ml.