Broadband ultrafast 2D NMR spectroscopy for online monitoring in continuous flow.

Flow NMR is a powerful tool to monitor chemical reactions under realistic conditions. Here, we describe ultrafast (UF) 2D NMR schemes that make it possible to acquire broadband homonuclear 2D NMR spectra in 90 seconds or less for a continuously flowing sample. An interleaved acquisition strategy is used to address the spectral width limitation of UF 2D NMR. We show how, for a flowing sample, the use of a transverse axis for spatial encoding makes it possible to achieve the very high scan-to-scan stability required for interleaved acquisition. We also describe an optimised solvent suppression strategy that is effective for interleaved acquisition in continuous flow. These developments open the way to online monitoring with flow 2D NMR at high time resolution, as we illustrate with the monitoring of an organocatalysed condensation reaction.

Accounting for gradient non-uniformity in spatially-encoded diffusion-ordered NMR spectroscopy.

Diffusion-ordered NMR spectroscopy (DOSY) is a powerful tool for the analysis of mixtures. Spatially-encoded (SPEN) DOSY makes it possible to collect a complete DOSY data set in a single scan, through spatial parallelisation of the gradient dimension. One limitation of current SPEN DOSY experiments is that the data is analysed assuming that the field gradient is uniform over the sample. This is usually not the case for high resolution NMR probes, and even less for triple-axis gradient probes. In this work, we have developed methods to account for gradient non-uniformity in the processing of SPEN DOSY experiment. We have first mapped the field gradient, using a stimulated echo (STE) NMR sequence with a weak readout gradient. We have then modified the calculation of the position-dependent effective gradient pulse area that is used in the analysis of SPEN DOSY data. The resulting model was validated through numerical simulations. A comparison of results obtained with and without inclusion of the effect of non-uniform gradients shows that the proposed approach increases the accuracy of SPEN DOSY experiments.

In-line Multidimensional NMR Monitoring of Photochemical Flow Reactions.

This work demonstrates the in-line monitoring of a flow photochemical reaction using 1D and ultrafast 2D NMR methods at high magnetic field. The reaction mixture exiting the flow reactor is flown through the NMR spectrometer and directly analyzed. In the case of simple substrates, suitable information can be obtained through 1D 1 H spectra, but for molecules of higher complexity the use of 2D experiments is key to address signal overlaps and assignment issues. Here we show the usefulness of ultrafast 2D COSY experiments acquired in 70 s or less, for the in-line monitoring of photochemical reactions, and the possibility to obtain reliable quantitative information. This is a powerful framework to, for example, efficiently screen reaction conditions.

Ultrafast 2D NMR for the analysis of complex mixtures.

2D NMR is extensively used in many different fields, and its potential for the study of complex biochemical or chemical mixtures has been widely demonstrated. 2D NMR gives the ability to resolve peaks that overlap in 1D spectra, while providing both structural and quantitative information. However, complex mixtures are often analysed in situations where the data acquisition time is a crucial limitation, due to an ongoing chemical reaction or a moving sample from a hyphenated technique, or to the high-throughput requirement associated with large sample collections. Among the great diversity of available fast 2D methods, ultrafast (or single-scan) 2D NMR is probably the most general and versatile approach for complex mixture analysis. Indeed, ultrafast NMR has undergone an impressive number of methodological developments that have helped turn it into an efficient analytical tool, and numerous applications to the analysis of mixtures have been reported. This review first summarizes the main concepts, features and practical limitations of ultrafast 2D NMR, as well as the methodological developments that improved its analytical potential. Then, a detailed description of the main applications of ultrafast 2D NMR to mixture analysis is given. The two major application fields of ultrafast 2D NMR are first covered, i.e., reaction/process monitoring and metabolomics. Then, the potential of ultrafast 2D NMR for the analysis of hyperpolarized mixtures is described, as well as recent developments in oriented media. This review focuses on high-resolution liquid-state 2D experiments (including benchtop NMR) that include at least one spectroscopic dimension (i.e., 2D spectroscopy and DOSY) but does not cover in depth applications without spectral resolution and/or in inhomogeneous fields.

Online Reaction Monitoring with Fast and Flow-Compatible Diffusion NMR Spectroscopy.

Online monitoring by flow NMR spectroscopy is a powerful approach to study chemical reactions and processes, which can provide mechanistic understanding, and drive optimisations. However, some of the most useful methods for mixture analysis and reaction monitoring are not directly applicable in flow conditions. This is the case of classic diffusion-ordered NMR spectroscopy (DOSY) methods, which can be used to separate the spectral information for mixture's components. We describe a fast and flow-compatible diffusion NMR experiment that makes it possible to collect accurate diffusion data for samples flowing at up to 3 mL/min. We use it to monitor the synthesis of a Schiff base with a flow-tube with a time resolution of approximately 2 minutes. The one-shot flow-compatible diffusion NMR described here open many avenues for reaction monitoring applications.

Phenyl Silicates with Substituted Catecholate Ligands: Synthesis, Structural Studies and Reactivity.

While the generation of aryl radicals by photoredox catalysis under reductive conditions is well documented, it has remained challenging under an oxidative pathway. Because of the easy photo-oxidation of alkyl bis-catecholato silicates, a general study of phenyl silicates bearing substituted catecholate ligands has been achieved. The newly synthesized phenyl silicates have been fully characterized, and their reactivity has been explored. It was found that, thanks to the substitution of the catecholate moiety, notably with the 4-cyanocatecholato ligand, the phenyl radical could be generated and trapped. Computational studies provided a rationale for these findings.

A simple and fast liquid chromatography tandem mass spectrometry method to determine cyclosporine A concentrations in endomyocardial biopsies.

Measuring cyclosporine A (CsA), an immunosuppressive drug used to prevent heart transplant rejection, concentrations in myocardial biopsies might be more informative than its measurement in whole blood. Therefore, a fast, accurate and reproductive method to determine CsA concentration in this complex matrix is needed. We report the validation of a liquid chromatography tandem mass spectrometry method to measure CsA concentration in heart parenchyma, applicable to everyday practice. The method was found to be precise, accurate, reproducible, specific of CsA, and without any matrix effect or carry-over. The lower limit of quantification was 50 pg of CsA in myocardium. The method was linear up to 2000 pg of CsA in myocardium. Samples were found stable for one year at - 80 °C. At last, 40 drugs which could be prescribed to heart transplant recipients were tested with the method and showed no interference with CsA signal. The method was suitable to quantify CsA in endomyocardial biopsies from heart transplanted patients. This method allows designing clinical studies aiming at exploring the relationship between CsA intra-graft concentrations and outcome.

Hierarchical Self-Assembly of Polyoxometalate-Based Organo Palladium(II) Metallomacrocycles via Electrostatic Interactions.

The design and synthesis of a supramolecular square composed of polyoxometalate-based hybrid donors and ethylenediamine palladium(II) nodes are reported. The structure of the metallomacrocycle scaffold was inferred by diffusion NMR, small-angle X-ray scattering (SAXS), and molecular modeling. The metallomacrocycle scaffold that contains negatively and positively charged subunits can further self-assemble owing to a competition between the solvation energy of the discrete species and intermolecular electrostatic interactions. When the dissociating character of the solvent was lowered or when in the presence of a protic solvent, different types of multiscale organizations (vesicles and pseudo-1D structures) were selectively formed and were characterized by SAXS and transmission electron microscopy.

Photochromism and Dual-Color Fluorescence in a Polyoxometalate-Benzospiropyran Molecular Switch.

The photophysical properties of a Keggin-type polyoxometalate (POM) covalently bounded to a benzospiropyran (BSPR) unit have been investigated. These studies reveal that both closed and open forms are emissive with distinct spectral features (λem (closed form)=530 nm, λem (open form)=670 nm) and that the fluorescence of the BSPR unit of the hybrid is considerably enhanced compared to BSPR parent compounds. While the fluorescence excitation energy of the BSPR reference compounds (370 nm) is close to the intense absorption responsible of the photochromic character (350 nm), the fluorescence excitation of the hybrid is shifted to lower energy (400 nm), improving the population of the emissive state. Combined NOESY NMR and theoretical calculations of the closed form of the hybrid give an intimate understanding of the conformation adopted by the hybrid and show that the nitroaryl moieties of the BSPR is folded toward the POM, which should affect the electronic properties of the BSPR.

Dramatic reduction of clindamycin serum concentration in staphylococcal osteoarticular infection patients treated with the oral clindamycin-rifampicin combination.

OBJECTIVES: Pharmacokinetics of clindamycin in combination with rifampicin or levofloxacin were prospectively evaluated for the oral treatment of severe staphylococcal osteo articular infections. METHODS: Thirty-four patients (25 males, 9 females), with a mean age of 52.4 ± 17 years (range, 24-81 years), were randomly assigned either to the clindamycin-rifampicin or to the clindamycin-levofloxacin arm (control), following surgical debridement and intravenous adapted treatment. Trough and peak serum concentrations of clindamycin were measured at day-1 (D1), D15 and D30 of oral treatment. Cure was evaluated at a minimum of one year after the initiation of treatment. RESULTS: The oral treatment was interrupted in 4 cases because of adverse events. Mean trough and peak serum concentrations of clindamycin in the clindamycin-rifampicin arm were lower than in the clindamycin-levofloxacin arm during the time of oral antibiotic regimen (0.79 ± 0.3 µg/ml vs 4.7 ± 1.2 µg/ml, p < 0.001, and 3.48 ± 1.1 µg/ml vs 10.2 ± 1.8 µg/ml, p < 0.001, respectively). A consistent decrease in clindamycin serum concentration was observed at each time-point of follow-up. At a mean of 23 ± 7.8 months (range, 12-47 months), 24 patients were available for clinical evaluation. No difference could be detected in the cure rates between the groups. CONCLUSIONS: Our results indicate a significant influence of rifampicin on clindamycin pharmacokinetics using the oral route. Clindamycin serum concentrations (trough and peak) were systematically below the recommended therapeutic ranges when associated with rifampicin, as opposed to the control. Considering the potential risk of selection of mutant resistant to clindamycin, we do not recommend the clindamycin-rifampicin combination in the oral treatment of severe staphylococcal osteoarticular infection, unless clindamycin serum concentration is thoroughly controlled. The study has been registered on the clinicaltrials.gov website under the number NCT 01500837.

[Medical treatment of the elderly in residential care: a multicenter cross-sectional study]. / Prescriptions médicamenteuses chez les personnes âgées en EHPAD: une étude transversale multicentrique.

OBJECTIVE: To retrospectively assess the quality of prescriptions in elderly patients prior the distribution of guidelines for geriatric drug prescriptions. METHODS: A cross-sectional study was conducted for one day in 2012 to investigate the quality of the prescriptions in 495 residents of 8 nursing homes. A 6 items-quality score was calculated, ranging from 0 (lowest quality) to 6 (highest quality). RESULTS: The median number of prescribed drugs was 8,5 per resident. Over a total of 4311 prescribed drugs, the average quality score was 4,96 ± 0,45; 4,54 ± 0,70 in computerized orders and 3,4 ± 1,02 in handwritten orders. Among 939 drugs considered as at high risk of inducing serious adverse reactions, monitoring was prescribed 154 times only (16,4%). CONCLUSIONS: A lack of drug monitoring was highlighted, especially for high risk drugs. The quality of prescription may be improved by the use of computerized orders.

Optimization of a microwave-assisted extraction of secondary metabolites from crustose lichens with quantitative spectrophotodensitometry analysis.

A focused and rapid microwave-assisted extraction (MAE) process was carried out and optimized for secondary metabolites from crustose lichens using Taguchi experimental design and quantitative analysis on TLC by a Camag((R)) spectrophotodensitometer. The procedure was improved by quantitative determination of norstictic acid (NA), a common depsidone isolated from Pertusaria pseudocorallina (Sw.) Arn. Various experimental parameters that can potentially affect the NA extraction yields including extraction time, irradiation power, volume and the percentage of tetrahydrofuran (THF) were optimized. Results suggest that THF percentage and solvent volume were statistically the most significant factors. The optimal conditions were determined as follows: THF level of 100%, solvent volume of 15mL, microwave power of 100W and extraction time of 7min. Compared to the reflux method, MAE showed a drastic reduction of extraction time (7min vs. 3h) and solvent consumption (15mL vs. 30mL). The NA in total yield was 90% using the two methods. The optimal conditions were applied to other crustose lichens, Aspicilia radiosa, Diploicia canescens and Ochrolechia parella for the extraction of NA, diploicine (DP) and variolaric acid (VA), with 83%, 90% and 95% of recovery, respectively.

Multiple dual-mode centrifugal partition chromatography as an efficient method for the purification of a mycosporine from a crude methanolic extract of Lichina pygmaea.

Centrifugal partition chromatography method was applied to the separation and purification of a crude methanolic extract of a cyanobacterial lichen, Lichina pygmaea. A multiple dual-mode was used to separate two compounds of interest, namely mycosporine-serinol and a glutamic acid derivative. These compounds are described here for the first time in a lichen. Their structures were identified by UV, IR, ESI-MS, (1)H NMR, (13)C NMR, and 2D NMR.

Stictic acid derivatives from the lichen Usnea articulata and their antioxidant activities.

Two new beta-orcinol depsidones, 1 and 2, together with 13 known compounds were isolated from the lichen Usnea articulata. The structures of 1 and 2 were elucidated by spectroscopic analyses and those of known compounds by comparison of their spectroscopic data with literature values or by direct comparison with authentic standards. Compounds 1, 2, and 5 exhibited moderate antiradical activity in the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. The depsidones 4 and 5 showed better superoxide anion scavenging activity (IC50 = 566 and 580 microM, respectively) than quercetin (IC50 = 754 microM).

Metabolites from the Lichen Ochrolechia parella growing under two different heliotropic conditions.

A new chloro-depsidone (1) and five known compounds, variolaric acid (2), lecanoric acid (3), alpha-alectoronic acid (4), atranorin (5), and ergosterol peroxide (6), have been isolated from the lichen Ochrolechia parella. The structure of compound 1 was elucidated by spectroscopic analysis. Additionally, the tautomeric equilibrium of compound 4 was investigated. In the present study, two specimens of this lichen, growing under different light conditions, were analyzed. The major compound in both samples was found to be 2, but the amount of this metabolite was significantly higher in the shaded specimen (0.76% w/w). The new compound parellin (1) predominated in the specimen grown under shady conditions, while atranorin (5) was found only in the sunlit specimen. The cytotoxic activities of 2, 4, and 6 against B16 melanoma cells were evaluated.

Pharmacomodulation of a sulfamide 5-HT6 receptor ligand.

A series of N-omega-aminoalkyl- or N-omega-amidinoalkyl-2,4,6-triisopropyl benzenesulfonamides has been synthesized and their respective affinity indices on 5-HT6 receptor determined. This evaluation clearly showed that the compounds possessing an arylpiperazine moiety or an amidine function exhibited good affinity for the model.