Photosensitized alkoxyamines as bicomponent radical photoinitiators

The photopolymerization ability of photosensitized alkoxyamines has been investigated. These compounds behave as interesting two‐component photoinitiators. Laser flash photolysis, electron spin resonance, and density functional theory allow to support the interactions encountered between the photosensitizer (benzophenone and isopropylthioxanthone) and the alkoxyamines (C? O bond breaking and hydrogen transfer) and the side reactions of the nitroxide radical with photosensitizer (electron transfer). © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 2910–2915, 2010     

Validation of chiral capillary electrophoresis-electrospray ionization-mass spectrometry methods for ecstasy and methadone in plasma

Due to its selectivity and sensitivity, CE coupled to MS (CE-MS) has evolved as a useful analytical tool for determining drugs and metabolites in biological samples. A generic CE-ESI/MS method was developed for the enantioselective determination of basic compounds in plasma. The use of protein precipitation (PP) prior to a hydrodynamic injection (HD) was well adapted to high-concentration samples (>1 ppm) and allowed high throughput. In contrast, the combination of liquid-liquid extraction (LLE) and electrokinetic injection (EK) was time-consuming but did allow detection at the ppb level. Both approaches were fully validated according to ICH guidelines and SFSTP protocols for two pharmaceutical compounds (ecstasy and methadone (MTD)). Deuterated internal standards (IS) in the analytical procedures were used and good quantitative performance was obtained in terms of trueness and precision (repeatability and intermediate precision) since accuracy profiles were within the acceptance limits (30% for biological assay). Methods were linear over the concentration range of 0.50-175 ng/mL and 0.25-5 microg/mL for LLE-EK and PP-HD procedures, respectively. The LLE-EK methodology was finally successfully applied to quantitation of ecstasy and MTD in real cases obtained from toxicology.     

Quantification of glucuronidated and sulfated steroids in human urine by ultra-high pressure liquid chromatography quadrupole time-of-flight mass spectrometry

The urinary steroid profile is constituted by anabolic androgenic steroids, including testosterone and its relatives, that are extensively metabolized into phase II sulfated or glucuronidated steroids. The use of liquid chromatography coupled to mass spectrometry (LC-MS) is an issue for the direct analysis of conjugated steroids, which can be used as urinary markers of exogenous steroid administration in doping analysis, without hydrolysis of the conjugated moiety. In this study, a sensitive and selective ultra high-pressure liquid chromatography coupled to quadrupole time-of-flight mass spectrometer (UHPLC-QTOF-MS) method was developed to quantify major urinary metabolites simultaneously after testosterone intake. The sample preparation of the urine (1 mL) was performed by solid-phase extraction on Oasis HLB sorbent using a 96-well plate format. The conjugated steroids were analyzed by UHPLC-QTOF-MS^E with a single-gradient elution of 36 min (including re-equilibration time) in the negative electrospray ionization mode. MS^E analysis involved parallel alternating acquisitions of both low- and high-collision energy functions. The method was validated and applied to samples collected from a clinical study performed with a group of healthy human volunteers who had taken testosterone, which were compared with samples from a placebo group. Quantitative results were also compared to GC-MS and LC-MS/MS measurements, and the correlations between data were found appropriate. The acquisition of full mass spectra over the entire mass range with QTOF mass analyzers gives promise of the opportunity to extend the steroid profile to a higher number of conjugated steroids.     

Nanostructuring at the surface of low‐energy lead‐implanted silicon by electron beam annealing

Low‐energy lead ion implantation and high‐temperature electron beam annealing were used to study the potential of producing Pb nanostructures on Si. Pb⁺ ions were implanted at high dose into p‐type (100) Si to the depth of 8.0 nm. The implanted samples were annealed under high vacuum conditions with an electron beam at 200–700 °C for 15 s. Rutherford Backscattering Spectrometry (RBS) shows rapid out‐diffusion of Pb atoms above 400 °C. However, some Pb atoms are still present in the near‐surface region after annealing the implanted samples at 700 °C. Lead nanostructures were found on samples annealed above 300 °C. Annealing the samples at 450 °C causes the formation of nanostructures as tall as 4.1 ± 0.1 nm. Many of these are arranged in ‘web‐like’ strings that extend over micrometer distances. Occasionally, much larger nano‐features (as wide as 500 nm in diameter, average height of 1.5 nm) appear in the centre of the strings. Annealing samples well above the melting point of lead results in randomly distributed small nanometer‐sized Si nano‐dots. Copyright © 2008 John Wiley & Sons, Ltd.     

Intermolecular interaction studies using small volumes

We present the use of 1-mm room-temperature probe technology to perform intermolecular interaction studies using chemical shift perturbation methods and saturation transfer difference (STD) spectroscopy using small sample volumes. The use of a small sample volume (5-10 μl) allows for an alternative titration protocol where individual samples are prepared for each titration point, rather than the usual protocol used for a 5-mm probe setup where the ligand is added consecutively to the solution containing the protein or host of interest. This allows for considerable economy in the consumption and cost of the protein and ligand amounts required for interaction studies. For titration experiments, the use of the 1-mm setup consumes less than 10% of the ligand amount required using a 5-mm setup. This is especially significant when complex ligands that are only available in limited quantities, typically because they are obtained from natural sources or through elaborate synthesis efforts, need to be investigated. While the use of smaller volumes does increase the measuring time, we demonstrate that the use of commercial small volume probes allows the study of interactions that would otherwise be impossible to address by NMR.     

Fast log P determination by ultra-high-pressure liquid chromatography coupled with UV and mass spectrometry detections

Ultra-high-pressure liquid chromatography (UHPLC) systems able to work with columns packed with sub-2 μm particles offer very fast methods to determine the lipophilicity of new chemical entities. The careful development of the most suitable experimental conditions presented here will help medicinal chemists for high-throughput screening (HTS) log P _oct measurements. The approach was optimized using a well-balanced set of 38 model compounds and a series of 28 basic compounds such as β-blockers, local anesthetics, piperazines, clonidine, and derivatives. Different organic modifiers and hybrid stationary phases packed with 1.7-μm particles were evaluated in isocratic as well as gradient modes, and the advantages and limitations of tested conditions pointed out. The UHPLC approach offered a significant enhancement over the classical HPLC methods, by a factor 50 in the lipophilicity determination throughput. The hyphenation of UHPLC with MS detection allowed a further increase in the throughput. Data and results reported herein prove that the UHPLC-MS method can represent a progress in the HTS-measurement of lipophilicity due to its speed (at least a factor of 500 with respect to HPLC approaches) and to an extended field of application. Figure The UHPLC approach described here greatly enhanced the time required for log P determination (5' min by compound using UV detection) and, at least, 8 compounds measured in a 5' run when Mass Spectrometry detection in used. These developments offer to medicinal chemists a high-throughput method to estimate the lipophilicity of NCEs Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. Experimental section for capillary electrophoresis (CE) measurements, list of the 38 compounds of the calibration set and solvatochromic analyses of the extrapolated retention factors and partition coefficients.     

Xanthates as synthetic equivalents of oxyacyl radicals: access to lactones under tin-free conditions

In addition to their utility in Barton-McCombie deoxygenations, xanthates can engage in 5-exo-trig radical cyclizations to afford lactones after oxidative workup. In this paper, we describe a tin-free protocol that provides direct access to lactones via hydrolysis of labile thioketal intermediates. Analysis of several systems of varying complexity reveals that the reaction is most applicable for constrained systems in which the reacting center is prepositioned near the radical-accepting alkene.     

Structure and X-ray conformation of pseudodesmins A and B, two new cyclic lipodepsipeptides from Pseudomonas bacteria

Two new cyclic lipodepsipeptides named pseudodesmins A and B have been isolated from Pseudomonas bacteria collected from the mucus layer in the skin of the black belly salamander. Both compounds show moderate antibacterial activity against Gram positive bacteria, including MRSA. Complete ¹H, ¹³C and ¹⁵N NMR assignment of both compounds afforded their covalent structure and served to guide the analysis of LC-MS and X-ray diffraction data from which the final stereochemistry could be established. Both molecules can be categorized as new members of the viscosin group of cyclic lipodepsipeptides.     

Analytical tools for the physicochemical profiling of drug candidates to predict absorption/distribution

The measurement of physicochemical properties at an early phase of drug discovery and development is crucial to reduce attrition rates due to poor biopharmaceutical properties. Among these properties, ionization, lipophilicity, solubility and permeability are mandatory to predict the pharmacokinetic behavior of NCEs (new chemical entities). Due to the high number of NCEs, the analytical tools used to measure these properties are automated and progressively adapted to high-throughput technologies. The present review is dedicated to experimental methods applied in the early drug discovery process for the determination of solubility, ionization constants, lipophilicity and permeability of small molecules. The principles and experimental conditions of the different methods are described, and important enhancements in terms of throughput are highlighted. Figure Scheme of the Drug Research Process.     

High performance silicon nanoparticle anode in fluoroethylene carbonate-based electrolyte for Li-ion batteries

Electrodes composed of silicon nanoparticles (SiNP) were prepared by slurry casting and then electrochemically tested in a fluoroethylene carbonate (FEC)-based electrolyte. The capacity retention after cycling was significantly improved compared to electrodes cycled in a traditional ethylene carbonate (EC)-based electrolyte.