Structure and dynamics of water at a clay surface from molecular dynamics simulation

We report a molecular dynamics study of the structure and dynamics of water at a clay surface. The negative charge of the surface and the presence of surface oxygen atoms perturbs water over two to three molecular layers, while the nature of the counterions (Na(+)or Cs(+)) has only a small effect. In the first molecular layer, approximately half of the water molecules are H-bonded to the surface. We also analyze the H-bond network between surface water molecules. The diffusion of water molecules along the surface is slowed down compared to the bulk case. As far as the orientational order and dynamics of the water dipole are concerned, only the component normal to the clay surface is perturbed. We investigate the surface H-bond formation and dissociation dynamics and their coupling to the release of molecules from the first molecular layer. We introduce a simple kinetic model in the spirit of Luzar and Chandler [Nature, 1996, 379, 55] to allow for a comparison with bulk water dynamics. This model semi-quantitatively reproduces the molecular simulation results and suggests that H-bond formation is faster with the surface than in the bulk, while H-bond dissociation is slower.     

Hydrogen-bond interactions of nicotine and acetylcholine salts: a combined crystallographic, spectroscopic, thermodynamic and theoretical study

The hydrogen-bond (HB) interactions of the monocharged active forms of nicotine and acetylcholine (ACh) have been compared theoretically by using density functional theory (DFT) calculations and experimentally on the basis of crystallographic observations and the measurement of equilibrium constants in solution. The 2,4,6-trinitrophenolate (picrate) counterion was used to determine the experimental HB basicity of the cations despite its potential multisite HB acceptor properties. The preferred HB interaction site of the ammonium picrate salts was determined from a survey of crystallographic data found in the Cambridge Structural Database (CSD) and is supported by theoretical calculations. Two distinct classes of ammonium groups were characterised depending on the absence (quaternary ammonium) or presence (tertiary, secondary and primary ammoniums) of an N(+)HO hydrogen bond linking the two ions. The crystal structure of nicotinium picrate was determined and compared with that of ACh. This analysis revealed the peculiar behaviour of the ammonium moiety of nicotinic acetylcholine receptor (nAChR) ligands towards the picrate anion. Dedicated methods have been developed to separate the individual contributions of the anion and cation accepting sites to the overall HB basicity of the ion pairs measured in solution. The HB basicities of the picrate anions associated with the two different ammonium classes were determined in dichloromethane solution by using several model ion pairs with non-basic ammonium cations. The experimental and theoretical studies performed on the nicotine and ACh cations consistently show the significant HB ability of the acceptor site of nAChR agonists in their charged form. Both the greater HB basicity of the pyridinic nitrogen over the carbonyl oxygen and the greater HB acidity of the N(+)H unit relative to N(+)CH could contribute to the higher affinity for nAChRs of nicotine-like ligands relative to ACh-like ligands.     

Multiplex target protein imaging in tissue sections by mass spectrometry--TAMSIM

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-MS) is becoming a popular tool for imaging histological sections. Currently, this technology is used to image naturally occurring molecules. Here we report a novel development for multiplex imaging of candidate proteins. Rather than detecting whatever molecules happen to be present and above the detection threshold in the desorption pixel, we attach photocleavable mass tags to antibodies to target proteins. 'Staining' of histological sections is carried out similarly to common immunohistochemical procedures with chemiluminescent or fluorescent detection using all antibodies of a multiplex simultaneously. Mass tags with discrete masses are released from their respective antibodies by a laser pulse at 355 nm without added matrix. After scanning, mass spectrometry images are created for the mass of each tag. In contrast to fluorescent tags, mass tags do not exhibit mutual quenching. Sections of healthy human pancreatic tissue were imaged to visualize synaptophysin in neuroendocrine cells, and sections from human lymph node and liver invaded by metastatic melanoma to localize the cancer markers PS100 and HMB45 simultaneously. All these proteins are below the detection threshold of direct MALDI-MS imaging. This method is termed TAMSIM for TArgeted multiplex Mass Spectrometry IMaging.     

Theoretical Study on the Photo-Oxidation and Photoreduction of an Azetidine Derivative as a Model of DNA Repair

Photocycloreversion plays a central role in the study of the repair of DNA lesions, reverting them into the original pyrimidine nucleobases. Particularly, among the proposed mechanisms for the repair of DNA (6-4) photoproducts by photolyases, it has been suggested that it takes place through an intermediate characterized by a four-membered heterocyclic oxetane or azetidine ring, whose opening requires the reduction of the fused nucleobases. The specific role of this electron transfer step and its impact on the ring opening energetics remain to be understood. These processes are studied herein by means of quantum-chemical calculations on the two azetidine stereoisomers obtained from photocycloaddition between 6-azauracil and cyclohexene. First, we analyze the efficiency of the electron-transfer processes by computing the redox properties of the azetidine isomers as well as those of a series of aromatic photosensitizers acting as photoreductants and photo-oxidants. We find certain stereodifferentiation favoring oxidation of the cis-isomer, in agreement with previous experimental data. Second, we determine the reaction profiles of the ring-opening mechanism of the cationic, neutral, and anionic systems and assess their feasibility based on their energy barrier heights and the stability of the reactants and products. Results show that oxidation largely decreases the ring-opening energy barrier for both stereoisomers, even though the process is forecast as too slow to be competitive. Conversely, one-electron reduction dramatically facilitates the ring opening of the azetidine heterocycle. Considering the overall quantum-chemistry findings, N,N-dimethylaniline is proposed as an efficient photosensitizer to trigger the photoinduced cycloreversion of the DNA lesion model.     

Triplet excited fluoroquinolones as mediators for thymine cyclobutane dimer formation in DNA

A series of fluoroquinolones (FQs), including enoxacin (ENX), pefloxacin (PFX), norfloxacin (NFX), its N(4')-acetyl derivative (ANFX), ofloxacin (OFX), and rufloxacin (RFX) have been investigated to determine their potential as DNA photosensitizers via thymine cyclobutane dimer (T<>T) formation in DNA. At fluoroquinolone concentrations and light doses insufficient to produce direct single strand breaks, ENX, PFX, and NFX were able to produce T<>T dimers in DNA, revealed by enzymatic treatment with T4 endonuclease V. By contrast, ANFX, OFX, and RFX were inefficient in this assay. The absolute values of the triplet energies of ENX, PFX, NFX, ANFX, OFX, and RFX were estimated by means of laser flash photolysis, using flurbiprofen, 4-biphenylcarboxylic acid, and naproxen as energy acceptors. They were found to be 273, 269, 269, 265, 262, and 253 kJ/mol, respectively. Other triplet excited state properties of the FQs, including quantum yields and lifetimes, were also studied. All the results indicate that the threshold ET value required for a given compound to become a potential DNA photosensitizer via T<>T formation is in the range defined by the triplet energies of NFX and ANFX (265-269 kJ/mol). This provides the basis for an alert rule: any chemical (drugs, cosmetics, pesticides, etc.) with higher ET has to be considered with regard to its potential photogenotoxicity.     

Modelling of toluene solid-phase microextraction for indoor air sampling

Solid-phase microextraction (SPME) is a convenient and efficient sampling technique recently applied to indoor air analysis. We propose here a theoretical model of the adsorption kinetics of toluene on SPME fibre under static extraction conditions. We discuss the effects of sampling volume and initial concentration of analyte on the adsorption kinetics. This model is used to estimate the limits of detection taking into account operating conditions and to calculate theoretical calibration curves. Results of comparison with experimental data are encouraging: only 11% difference for calibration curves and 30% for the estimation of the limit of detection. On the basis of this kinetics model, the solid concentration gradient in the Carboxen coating was modelled with Fick’s second law of diffusion in unsteady-state mass-transfer mode. Mass diffusion from the gas sample to the SPME fibre was also investigated. It was shown that diffusion is the limiting step of the mass-transfer process in the static mode. Thus, the model developed, allows a better understanding of adsorption on Carboxen fibre and in the future could be a useful tool for cheap and time-saving development of SPME methods and the estimation of sampling performance. Figure PDMS/Carboxen SPME fibre (scanning electron microscopy – magnification x 220)     

Efficient enantioselective synthesis of 3-aminochroman derivatives through ruthenium-Synphos catalyzed asymmetric hydrogenation

A highly enantioselective asymmetric hydrogenation of various trisubstituted enamides derived from chroman-3-ones promoted by cationic Ru-Synphos catalysts is reported. This atom-economical and clean method provides an efficient route to optically active 3-aminochroman derivatives, which are important pharmacophores found in numerous drug candidates, in high chemical yields and enantiomeric excesses up to 96%.     

Pre-study and in-study validation of a SPE-LC-MS-MS method for the determination of 5-S-cysteinyldopa, a melanoma biomarker, in human plasma

The incidence of malignant melanona has increased over the past decades, particularly in Caucasian population. This disease presents defavourable prognosis in terms of survey, especially when detection occurs at the metastatic phase. Reliable analytical methods for biomarker determination are thus an interesting tool in pathology detection and follow-up. In this context, a method using SPE-LC-ESI-MS-MS for the determination of 5-S-cysteinyldopa (5-SCD) in human plasma was optimized. The presence of matrix effect was investigated in details while 5-SCD stability was studied according to FDA requirements for the validation of bioanalytical methods. Pre-study and in-study validations of the entire method were then successfully performed by applying the approach based on total measurement error and accuracy profiles over a concentration ranges from 1.6 to 200 ng/ml. Good results with respect to accuracy, trueness and precision were obtained. The maximum risk of observing future measurements falling outside the acceptance limits during routine analysis was also estimated.