The application of high-resolution mass spectrometry-based data-mining tools in tandem to metabolite profiling of a triple drug combination in humans

Patients are usually exposed to multiple drugs, and metabolite profiling of each drug in complex biological matrices is a big challenge. This study presented a new application of an improved high resolution mass spectrometry (HRMS)-based data-mining tools in tandem to fast and comprehensive metabolite identification of combination drugs in human. The model drug combination was metronidazole-pantoprazole-clarithromycin (MET-PAN-CLAR), which is widely used in clinic to treat ulcers caused by Helicobacter pylori. First, mass defect filter (MDF), as a targeted data processing tool, was able to recover all relevant metabolites of MET-PAN-CLAR in human plasma and urine from the full-scan MS dataset when appropriate MDF templates for each drug were defined. Second, the accurate mass-based background subtraction (BS), as an untargeted data-mining tool, worked effectively except for several trace metabolites, which were buried in the remaining background signals. Third, an integrated strategy, i.e., untargeted BS followed by improved MDF, was effective for metabolite identification of MET-PAN-CLAR. Most metabolites except for trace ones were found in the first step of BS-processed datasets, and the results led to the setup of appropriate metabolite MDF template for the subsequent MDF data processing. Trace metabolites were further recovered by MDF, which used both common MDF templates and the novel metabolite-based MDF templates. As a result, a total of 44 metabolites or related components were found for MET-PAN-CLAR in human plasma and urine using the integrated strategy. New metabolic pathways such as N-glucuronidation of PAN and dehydrogenation of CLAR were found. This study demonstrated that the combination of accurate mass-based multiple data-mining techniques in tandem, i.e., untargeted background subtraction followed by targeted mass defect filtering, can be a valuable tool for rapid metabolite profiling of combination drugs in vivo.     

Solid‐phase extraction based on a molecularly imprinted polymer for the selective determination of four benzophenones in tap and river water

This work reports the preparation of molecularly imprinted polymer particles for the selective extraction and determination of four benzophenones from aqueous media. The polymer was prepared by using 4‐vinylpridine as functional monomer, ethylene glycol dimethacrylate as cross‐linker, acetonitrile as porogenic solvent and 2,2’,4,4’‐tetrehydroxybenzophenone as template. Good specific adsorption capacity (Q_max = 27.90 μmol/g) for 2,2’,4,4’‐tetrehydroxybenzophenone was obtained in the sorption experiment and good class selectivity for 2,2’,4,4’‐tetrehydroxybenzophenone, 2,4‐dihydroxybenzophenone, 2,2’‐dihydroxy‐4‐methoxybenzophenone, 2,2’‐dehydroxy‐4,4’‐dimethoxybenzophenone was demonstrated by the chromatographic evaluation experiment. Factors affecting the extraction efficiency of the molecularly imprinted solid‐phase extraction procedure were investigated systematically. An accurate and sensitive analytical method based on the molecularly imprinted solid‐phase extraction coupled with high‐performance liquid chromatography and diode array detection has been successfully developed for the simultaneous determination of four benzophenones from tap water and river water with method detection limits of 0.25–0.72 ng/mL. The recoveries of benzophenones for water samples at two spiking levels (500 and 5000 ng/mL for each benzophenone) were in the range of 86.9–103.3% with relative standard deviations (n = 3) below 9.2%.     

Messung der dynamischen Eigenschaften verdünnter Polymerlösungen

Zusammenfassung Ein neuartiges Rheometer zur Ermittlung der rheologischen Eigenschaften von Polymerlösungen im linear-viskoelastischen Bereich wird vorgestellt. Durch Anwendung der Laser-Doppler-Anemometrie, die eine im hydro-dynamischen Sinn störungsfreie Meßmethode darstellt, ist es möglich, niedrig-viskose bis hin zu wasserähnlichen Proben zu vermessen.Zur Bewältigung der in großer Zahl anfallenden Daten und Rechenoperationen findet ein Mikrocomputer-System Verwendung. Es erledigt im einzelnen die Aufgaben Versuchsablauf-Steuerung, Meßwerterfassung, Auswertung, Dokumentation und graphische Darstellung der Ergebnisse.Anhand von Messungen an newtonschen Flüssigkeiten werden der Funktionsnachweis erbracht und die Betriebsbereiche der Ringspaltsysteme unterschiedlichen Durchmessers ermittelt.Die viskoelastischen Eigenschaften von wäßrigen Polyethylenoxid- und Polyacrylamid-Lösungen niedriger Viskosität lassen sich über einen Frequenzbereich von 0,1 bis 100 Hz messen. Die Ergebnisse werden mit Hilfe der komplexen Viskositätsfunktion dargestellt. Daraus läßt sich als gleichwertige Darstellung das diskrete Relaxationsspektrum eines konkreten Stoffgesetzes gewinnen.

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A novel rheometer for determining the elastic characteristics of polymeric solutions in the linear-viscoelastic region is described. Laser-Doppler anemometry, which does not introduce hydrodynamic disturbances, is used to enable low viscosity liquids including water-like samples to be measured.A microcomputer system is utilized to control the experiments, store and analyse the measured data, and provide graphical representations of the results. Measurements on Newtonian liquids verified the validity of the method and allowed the operational regions of the annulus systems with different diameters to be determined.The elastic characteristics of low viscosity aqueous solutions of polyethyleneoxide and polyacrylamide can be measured at frequencies from 0.1 to 100 Hz. The results are presented using the complex viscosity function. As a result the discrete relaxation spectrum of a special material law can be obtained as an equivalent representation.

     

Synthesis and Anti‐HIV Activity of Triazolo‐Fused,Medium‐Sized Cyclic Nucleoside Analogs Prepared by an Intramolecular Huisgen 1,3‐Dipolar Cycloaddition

Medium‐sized cyclic nucleosides containing a fused triazole ring were synthesized via intramolecular Huisgen 1,3‐dipolar cycloadditon reaction. 2′,3′‐seco‐Uridine was employed as the key intermediate for the introduction of azido and alkynyl moieties in the defined positions of the reaction precursors. The cycloaddition reactions were achieved in high yields by heating the precursor in refluxing toluene. The uracil base in these target compounds was successfully transformed to the corresponding cytosine. The synthesized compounds were evaluated in a MAGI assay for their anti‐HIV activities, and in a H9 T lymphocytes assay for their cell toxicities.     

Electrochemical detection of ultratrace nitroaromatic explosives using ordered mesoporous carbon

A sensitive electrochemical sensor has been fabricated to detect ultratrace nitroaromatic explosives using ordered mesoporus carbon (OMC). OMC was synthesized and characterized by scanning electron microscopy, transmission electron microscopy and nitrogen adsorption/desorption measurements. Glassy carbon electrodes functionalized with OMC show high sensitivity of 62.7 μA cm⁻² per ppb towards 2,4,6-trinitrotoluene (TNT). By comparison with other materials such as carbon nanotubes and ordered mesoporous silica, it is found that the high performance of OMC toward sensing TNT is attributed to its large specific surface area and fast electron transfer capability. As low as 0.2 ppb TNT, 1 ppb 2,4-dinitrotoluene and 1 ppb 1,3-dinitrobenzene can be detected on OMC based electrodes. This work renders new opportunities to detect ultratrace explosives for applications of environment protections and home securities against chemical warfare agents.     

Impact of sugar stereochemistry on natural killer T cell stimulation by bacterial glycolipids

Natural killer T (NKT) cells recognize glycolipids produced by Sphingomonas bacteria, and these glycolipids contain C6-oxidized sugars, either glucuronic acid or galacturonic acid, linked to ceramides. Glycolipids with gluco stereochemistry are the most prevalent. Multiple studies have demonstrated that galactosylceramides are more potent stimulators of NKT cells than their glucose isomers. To determine if this stereoselectivity is retained in the context of the C6-oxidized sugars found in bacterial glycolipids, we prepared two sets of gluco and galacto-glycolipids oxidized at their C6 positions and compared their NKT stimulatory properties. In the context of carboxylic acid groups at C6, gluco stereochemistry gave the more potent responses. We also prepared bacterial glycolipids containing more complex ceramide groups to determine if these chains impact NKT cell responses.     

Pharmacokinetic Study of ZS-1, a Targeted Peptide to NCI-H1299, in Rats Following Intravenous Administration

To investigate the pharmacokinetics of ZS-1 following intravenous injection in rats, ZS-1 was administered at doses of 20, 30 and 45 mg kg^?1, respectively. Blood samples were collected at 0.5, 3, 8, 12, 15, 20, 30, 40 and 45 min. ZS-1 in rat plasma was measured by LC. The limit of detection (LOD) was 0.02 μg mL^?1. The relative standard deviation (RSD) of intra- and inter-day precisions were <10%, and the accuracy of intra- and inter-day were >94%. The mean extraction recovery of ZS-1 was 86.1%. After intravenous injection at doses of 20, 30 and 45 mg kg^?1, the concentration–time curves of ZS-1 fitted well to one compartment model. Area under the concentration–time curves (AUC) increased with dose. Clearance rates (CL) and elimination half-lives (T _1/2) had no significant difference between different dose groups (P > 0.05). ZS-1 was stable in plasma after at 25 °C for 2, 4, 6 h, after three freeze–thaw cycles, after ?20 °C for a month, and after ?80 °C for 3 months. The accuracy of ZS-1 was between 96.8 and 106.9%. The results indicated there was no significant degradation. These data indicated that the method for analysis of ZS-1 was reliable and the pharmacokinetic data could guide dosing regimens to be tested in future clinical pharmacokinetic study.     

Organic dye bearing asymmetric double donor-π-acceptor chains for dye-sensitized solar cells

A novel efficient metal free sensitizer containing asymmetric double donor-π-acceptor chains (DC) was synthesized for dye-sensitized solar cells (DSSCs). Comparing to 3.80%, 4.40% and 4.64% for the DSSCs based on the dyes with single chain (SC1, SC2) and cosensitizers (SC1 + SC2), the overall conversion efficiency reaches 6.06% for DC-sensitized solar cells as a result of its longer electron lifetime and higher incident monochromatic photon-to-current conversion efficiency.     

Precursor-directed fungal generation of novel halogenated chaetoglobosins with more preferable immunosuppressive action

Precursor-fed cultivation of endophytic Chaetomium globosum 1C51 afforded nine novel "unnatural" halogenated chaetoglobosins including those with more preferable immunosuppressive activity.