Enhanced mass resolution method development, validation and assay application to support preclinical studies of a new drug candidate

A very highly sensitive and highly selective liquid chromatographic/tandem mass spectrometric (LC/MS/MS) method was developed to evaluate and quantify a new drug candidate in different biological matrices. Following a simple plasma protein precipitation using acetonitrile, the post-treatment samples were analyzed on a C18 column interfaced with a new generation of triple-quadrupole mass spectrometer. The recently introduced triple-quadrupole mass spectrometer, the TSQ Quantum Ultra, with enhanced mass-resolution capability, demonstrated improved sensitivity (0.05 ng/mL), coupled with suitable accuracy and precision, over a broad linear dynamic range (0.05-1000 ng/mL). A comparison of the assay performance data (dynamic range, calibration curve equation, precision and accuracy) of the enhanced resolution method against a unit resolution method under optimized conditions showed the performance improvement of the enhanced mass resolution method for bioanalytical high-throughput applications. The enhanced mass resolution method herein described was successfully applied to the evaluation of the pharmacokinetic profile of a new drug candidate in rat, rabbit and dog plasma samples.     

Boron 1s photoelectron spectrum of 11BF3: vibrational structure and linewidth

The boron 1s photoelectron spectrum of (11)BF(3) has been measured at a photon energy of 400 eV and a resolution of about 55 meV. The pronounced vibrational structure seen in the spectrum has been analyzed to give the harmonic and anharmonic vibrational frequencies of the symmetric stretching mode, 128.1 and 0.15 meV, as well as the change in equilibrium BF bond length upon ionization, -5.83 pm. A similar change in bond length has been observed for PF(3) and SiF(4), but a much smaller change for CF(4). Theoretical calculations for BF(3) that include the effects of electron correlation give results that are in reasonable accord with the experimental values. The Lorentzian (lifetime) width of the boron 1s core hole in BF(3) is found to be 72 meV, comparable to the value of 77 meV that has been reported for CF(4).     

One-pot synthesis of new symmetric and asymmetric xanthene dyes

Symmetric and asymmetric xanthene dyes have been prepared by a convenient one-step procedure from aldehyde and diol or m-aminophenol precursors using concentrated phosphoric acid as a solvent. This protocol provides access to water-soluble dyes with large Stoke’s shifts and far-red fluorescence emission. These compounds are envisioned as components of fluorescence-based sensors for a variety of imaging applications.     

Microfluidic devices for energy conversion: planar integration and performance of a passive, fully immersed H2-O2 fuel cell

We describe the fabrication and performance of a passive, microfluidics-based H2-O2 microfluidic fuel cell using thin film Pt electrodes embedded in a poly(dimethylsiloxane) (PDMS) device. The electrode array is fully immersed in a liquid electrolyte confined inside the microchannel network, which serves also as a thin gas-permeable membrane through which the reactants are fed to the electrodes. The cell operates at room temperature with a maximum power density of around 700 microW/cm(2), while its performance, as recorded by monitoring the corresponding polarization curves and the power density plots, is affected by the pH of the electrolyte, its concentration, the surface area of the Pt electrodes, and the thickness of the PDMS membrane. The best results were obtained in basic solutions using electrochemically roughened Pt electrodes, the roughness factor, R(f), of which was around 90 relative to a smooth Pt film. In addition, the operating lifetime of the fuel cell was found to be longer for the one using higher surface area electrodes.     

Ring-borylated 15-electron and 17-electron ansa-chromocene complexes, their physical properties and molecular structures

A detailed study of the thermal decomposition of the zwitterionic, ring-borylated ansa-chromocene hydrido carbonyl complex [Cr(CO)H{Me(4)C(2)(C(5)H(4))[C(5)H(3)B(C(6)F(5))(3)]}] (2) is described. This complex is formed in the reaction between [Cr(CO){Me(4)C(2)(C(5)H(4))(2)}] (1) and B(C(6)F(5))(3) in toluene at -78 degrees C. Above -25 degrees C, 2 decomposes to a 50:50 mixture of the low-spin, 17e Cr(III) complexes [Cr(CO){Me(4)C(2)(C(5)H(4))[C(5)H(3)B(C(6)F(5))(3)]}] (3b) and [Cr(CO){Me(4)C(2)(C(5)H(4))(2)}][HB(C(6)F(5))(3)] (4). Carbon monoxide elimination from 3 b generates high-spin, 15 e [Cr{Me(4)C(2)(C(5)H(4))[C(5)H(3)B(C(6)F(5))(3)]}] (3a), which coordinates two other electron-donating ligands, such as xylyl isocyanide, PMe3, and PPh(2)Me to form the low-spin, 17 e electron complexes 3c, 3d, and 3e, respectively. High-spin, 15 e [Cr{Me(4)C(2)(C(5)H(4))(2)}][HB(C(6)F(5))(3)] (5) is generated by heating 3 b in toluene at 100 degrees C and periodically removing the evolved CO. Efforts to isolate more than a few X-ray quality crystals of 5 were thwarted by its tendency to form an insoluble precipitate (6) with the same molecular formula. Heating the solution of 5 at 120 degrees C results in its partial conversion (ca. 28 %) to 3a, thereby allowing the formation of 3a in yields as high as 74 % from the reaction between 1 and B(C(6)F(5))(3). The X-ray crystal structures of 3 b-e and 5 are described. Cyclic voltammetry measurements on 3 a-e reveal a dramatic reduction in the redox potentials of the complexes relative to their non-borylated analogues. DFT calculations show that this is due primarily to electrostatic stabilization of the oxidized species by the negatively charged borylate group. EPR and 19F NMR spectroscopy allow 3a to be distinguished from its Lewis base adducts 3 b-e and reveal the relative affinities of different Lewis bases for the chromium.     

Ab initio investigations of the bound rovibrational levels of NeH 2 + , NeHD+, and NeD 2 +

Summary Bound rovibrational levels have been calculated for NeH ₂ ⁺ , NeHD⁺, and NeD ₂ ⁺ using three recent fits to an accurateab initio PES. The NeH ₂ ⁺ molecule behaves essentially as a linear molecule, the predicted rotational constant is 2.57 cm^–1. The fundamental frequencies are 811, 1189, and 1748 cm^–1 for the Ne-H ₂ ⁺ stretch, the Ne-H ₂ ⁺ bend and H ₂ ⁺ stretching modes, respectively.Dedicated to the 60th birthday of Prof. W. Kutzelnigg, Bochum     

Addressing the metabolic activation potential of new leads in drug discovery: a case study using ion trap mass spectrometry and tritium labeling techniques

Metabolic activation of drug candidates to electrophilic reactive metabolites that can covalently modify cellular macromolecules may result in acute and/or idiosyncratic immune system-mediated toxicities in humans. This presents a significant potential liability for the future development of these compounds as safe therapeutic agents. We present here an example of an approach where sites of metabolic activation within a new drug candidate series were rapidly identified using online liquid chromatography/multi-stage mass spectrometry on an ion trap mass spectrometer. This was accomplished by trapping the reactive intermediates formed upon incubation of compounds with rat and human liver microsomes as their corresponding glutathione conjugates and mass spectral characterization of these thiol adducts. Based on the structures of the GSH adducts identified, potential sites and mechanisms of bioactivation within the chemical structure were proposed. These metabolism studies were interfaced with iterative structural modifications of the chemical series in order to block these bioactivation sites within the molecule. This strategy led to a significant reduction in the propensity of the compounds to undergo metabolic activation as evidenced by reductions in the irreversible binding of radioactivity to liver microsomal material upon incubation of tritium-labeled compounds with this in vitro system. With the efficiency and throughput achievable with such an approach, it appears feasible to identify and address the metabolic activation potential of new drug leads during routine metabolite identification studies in an early drug discovery setting.     

Dewetting of unreacted epoxy/amine mixtures on silica

We employ a direct method, time-of-flight secondary ion mass spectroscopy (ToF-SIMS), to determine experimentally the chemical compositions of the wetted and dewetted regions of an uncured epoxy thin film. Determining the composition of the dewetted region indicated the presence of a very thin sublayer of resin in what was thought to be a region devoid of resin. The capability of ToF-SIMS to probe small 65 x 65 microm(2) areas of the surface has permitted us to directly compare the SIMS spectra of the wetted and dewetted regions to the survey spectra of the reactants. This may indicate the strength of resin/silica interactions, which determine interface formation and properties.     

Nuclear magnetic resonance investigation of dynamics in poly(ethylene oxide)-based lithium polyether-ester-sulfonate ionomers

Nuclear magnetic resonance spectroscopy has been utilized to investigate the dynamics of poly(ethylene oxide)-based lithium sulfonate ionomer samples that have low glass transition temperatures. (1)H and (7)Li spin-lattice relaxation times (T(1)) of the bulk polymer and lithium ions, respectively, were measured and analyzed in samples with a range of ion contents. The temperature dependence of T(1) values along with the presence of minima in T(1) as a function of temperature enabled correlation times and activation energies to be obtained for both the segmental motion of the polymer backbone and the hopping motion of lithium cations. Similar activation energies for motion of both the polymer and lithium ions in the samples with lower ion content indicate that the polymer segmental motion and lithium ion hopping motion are correlated in these samples, even though lithium hopping is about ten times slower than the segmental motion. A divergent trend is observed for correlation times and activation energies of the highest ion content sample with 100% lithium sulfonation due to the presence of ionic aggregation. Details of the polymer and cation dynamics on the nanosecond timescale are discussed and complement the findings of X-ray scattering and quasi-elastic neutron scattering experiments.