Syntheses of 4′-spirocyclic phosphono-nucleosides as potential inhibitors of hepatitis C virus NS5B polymerase

To discover novel nucleosides as potential antiviral agents, 4′-spirocyclic phosphono-nucleosides were designed to mimic the monophosphate of R-1479, a known nucleoside inhibitor of HCV NS5B. Bypassing the first kinase step to nucleoside monophosphate is viewed as advantageous since this phosphorylation is often observed as the rate-limiting transformation to the active NTP for many nucleosides. Efficient synthetic routes were developed with a triphenylphosphine–iodine cyclization reaction as the key step to form the tetrahydrofuran 4′-spirocycle. The desired 4′-spirocyclic phosphono-cytidine analogs 12a, 12b, and 16 were prepared in 11 steps.     

Effect of Water Fraction on Rheological Properties of Waxy Crude Oil Emulsions

This article discusses the effect of water fraction on the rheological properties of waxy crude oil emulsions including gel point, yield stress, viscosity, and thixotropy. The experimental results reveal that the rheological behaviors of the w/o emulsion samples all intensify with the increase of water volume fraction within 60%. Of more significance is that a correlation for w/o emulsions between yield stress and water volume fraction is put forward with an average relative error of 6.75%. In addition, some mainstream viscosity prediction models of w/o emulsions are evaluated, and Elgibaly model is the best-fit for the emulsions in this study.     

The synthesis of a new cardiac sympathetic nerve imaging agent N-[11C]CH3-dopamine and biodistribution study

In this study, we synthesized and characterized N-[¹¹C]methyl-dopamine ([¹¹C]MDA) for cardiac sympathetic nerve imaging. [¹¹C]MDA was synthesized by direct N-methylation of dopamine with [¹¹C]methyl iodide and purified by semi-preparation reverse high pressure liquid chromatography (HPLC). The total synthesis time was 45 min including HPLC purification. The radiochemical yields of [¹¹C]MDA was 20 ± 3 %, without decay correction. The radiochemical purity was >98 % and the specific activity was about 50 GBq/mmol. The biological properties of [¹¹C]MDA were evaluated by biodistribution study in normal mice. PET imaging was performed in healthy Chinese mini-swines. Biodistribution study showed that [¹¹C]MDA had high myocardium uptake. PET/CT imaging showed [¹¹C]MDA had clear and symmetrical myocardium uptake, which was blocked obviously by injecting imipramine hydrochloride. [¹¹C]MDA would be a promising candidate of radiotracer for cardiac sympathetic nervous system imaging.     

Modified 2-window approach for rapid determination of 90Sr and 90Y at low quench level using liquid scintillation counting

⁹⁰Sr is a product of nuclear fission, the radioactivity of which can be determined by liquid scintillation counting (LSC). Because the LSC spectra of ⁹⁰Sr and its daughter ⁹⁰Y overlap each other, the following methods are usually used: (1) measuring immediately after ⁹⁰Sr/⁹⁰Y separation; (2) waiting to reach radioactive equilibrium; (3) adopting the conventional 2-window approach; and (4) using the spectra deconvolution technique. The first one requires ⁹⁰Sr/⁹⁰Y separation and immediate measurement; the second one is time-consuming; the third one is valid only for samples with the same quench level as the calibration standard; the last one is somewhat complicated, and in some cases it is not convenient to export the experimental data to some deconvolution software. Therefore, we have developed a modified 2-window approach to rapidly determine ⁹⁰Sr and ⁹⁰Y in either equilibrium or disequilibrium at low quench level. The key modification of the approach is to provide an LSC spectrum of pure ⁹⁰Y with the same quench level as the sample to be determined. This modification eliminates the need to conduct ⁹⁰Sr/⁹⁰Y separation for the sample itself, to prepare the quench curves, and to fit the LSC spectra with some deconvolution software.     

Radioactive 129I in surface water of the Celtic Sea

Relatively large amounts of radioactive iodine ¹²⁹I (T _1/2  = 15.7 Ma) have been documented in seawater such as the English Channel, the Irish Sea and the North Sea. Data on the concentration of the iodine isotopes in waters of the Celtic Sea are missing. Aiming to provide first ¹²⁹I data in the Celtic Sea and compare them with levels in the other close-by seawater bodies, surface seawater samples were analyzed for the determination of ¹²⁷I and ¹²⁹I concentrations. The results revealed a high level of ¹²⁹I in these waters and suggest strong influence by liquid discharges from La Hague and Sellafield reprocessing facilities. ¹²⁷I concentrations are rather constant while the ¹²⁹I/¹²⁷I ratio reaches up to 2.8 × 10^?8 (ranging from 10^?10 to 10^?8), which is 2–4 orders of magnitude higher than pre-nuclear era natural level. Transport of ¹²⁹I to the Celtic Sea is difficult to depict accurately since available data are sparse. Most likely, however, that discharges originated from La Hague may have more influence on the Celtic Sea ¹²⁹I concentrations than the Sellafield. Comprehensive surface water and depth profiles ¹²⁹I data will be needed in the future for assessment of environmental impact in the region.     

Adsorptive removal of La(III) from aqueous solutions with 8-hydroxyquinoline immobilized GMZ bentonite

Due to the low permeability, high swelling capacity and good retardation properties, bentonite has been considered as the main component of buffer/backfill material for high level radioactive wastes repository all over the world. The adsorptions of metal ion were widely investigated recently. In this presentation, we provide an easy-to-use method to immobilize 8-hydroxyquinoline onto the surface of bentonite for the use of adsorption studies of La(III) from the aqueous solution. The effects of various parameters such as contact time, pH of the solution, ionic strength and metal ion concentration on the adsorption were investigated by the batch experiments. The biggest adsorption capacity is 41.7 mg/g, higher than the value reported by our previous work which is performed by the raw bentonite. Langmuir isotherm fits the experimental data well and the adsorption follows pseudo-second-order kinetic model. In summary, 8-hydroxyquinoline immobilized GMZ bentonite is an effective adsorbent for the removal of La(III) from aqueous solutions.     

Combination of UHPLC/Q-TOF-MS,NMR spectroscopy,and ECD calculation for screening and identification of reactive metabolites of gentiopicroside in humans

The metabolic investigation of natural products is a great challenge because of unpredictable metabolic pathways, little knowledge on metabolic effects, and lack of recommended analytical methodology. Herein, a combined strategy based on ultrahigh-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UHPLC/Q-TOF-MS), nuclear magnetic resonance (NMR) spectroscopy, and electronic circular dichroism (ECD) calculation was developed and employed for the human metabolism study of gentiopicroside (GPS), a naturally hepato-protective iridoid glycoside. The whole metabolic study consisted of three major procedures. First, an improved UHPLC/Q-TOF-MS method was used to separate and detect a total of 15 GPS metabolites that were obtained from urine samples (0 to 72 h) of 12 healthy male participants after a single 50-mg oral dose of GPS. Second, a developed “MS-NMR-MS” method was applied to accurately identify molecular structures of the observed metabolites. Finally, given that the associated stereochemistry may be a crucial factor of the metabolic activation, the absolute configuration of the reactive metabolites was revealed through chemical calculations. Based on the combined use, a pair of diastereoisomers (G05 and G06) were experimentally addressed as the bioreactive metabolites of GPS, and the stereochemical determination was completed. Whereas several novel metabolic transformations, occurring via oxidation, N-heterocyclization and glucuronidation after deglycosylation, were also observed. The results indicated that GPS has to undergo in vivo metabolism-based activation to generate reactive molecules capable of processing its hepato-protective activity.

Simultaneous determination of chlorpyrifos and 3,5,6-trichloro-2-pyridinol in duck muscle by modified QuEChERS coupled to gas chromatography tandem mass spectrometry (GC-MS/MS)

A rapid, specific, and sensitive method based on modified quick, easy, cheap, effective, rugged, and safe (QuEChERS) coupled to gas chromatography tandem mass spectrometry (GC-MS/MS) was developed and validated for simultaneous determination of chlorpyrifos (CP) and its metabolite 3,5,6-trichloro-2-pyridinol (TCP) in duck muscle. The residues of CP and TCP were extracted by acidified acetonitrile. The fat layer of the extract was removed under ?20 °C, then the organic layer was evaporated. The analytes were derivatized by N-(tert-butyldimethylsilyl)-N-methyltrifluoroacetamide (MTBSTFA) and cleaned up by a mixture of 150 mg MgSO₄, 25 mg graphitized carbon black (GCB), and 50 mg N-propylethylenediamine (PSA) to remove interference. The final extract was analyzed by GC-MS/MS. Recovery values at the spiking concentrations ranged from 86.2 to 92.3 % for CP and from 74.8 to 81.8 % for TCP, with relative standard deviations (RSDs) lower than 9.5 and 12.3, respectively. The correlation coefficients of CP (from 2 to 2,000 μg/kg) and TCP (from 1 to 1,000 μg/kg) were equal to or higher than 0.998. The limits of detection (LODs) were 0.3 and 0.15 μg/kg, and the limits of quantification (LOQs) were 1.0 and 0.5 μg/kg for CP and TCP in duck muscle, respectively. The average intra- and inter-day accuracy ranged from 84.6 to 91.2 % for CP and 75.6 to 82.3 % for TCP, and the intra- and inter-day precisions were from 5.8 to 8.2 % for CP and 6.5 to 11.9 % for TCP. Furthermore, the CP and TCP residues in duck muscle samples were detected for dietary risk assessment using the validated method.

Tissue imaging and serum lipidomic profiling for screening potential biomarkers of thyroid tumors by matrix-assisted laser desorption/ionization-Fourier transform ion cyclotron resonance mass spectrometry

Changes in serum lipidome and in tissue lipidome are associated with cancer. In this study, tissue mass spectrometry imaging (MSI) and serum lipid profiling by matrix-assisted laser desorption/ionization-Fourier transform ion cyclotron resonance mass spectrometry (MALDI-FTICR MS) were performed to investigate significantly changed lipids in both tumor (malignant thyroid cancer (MTC) and benign thyroid tumor (BTT)) tissues and sera. Y-scatterplots of variable importance in the projection (VIP) values vs. fold change values indicate that change trends in the levels of ten lipids (i.e., phosphatidylcholine (PC)(34:1), PC(36:1), PC(38:6), phosphatidic acid (PA) (36:2), PA(36:3), PA(38:3), PA(38:4), PA(38:5), PA(40:5), and sphingomyelin (SM)(34:1)) in both tissues and sera from MTC patients, BTT patients, and normal individuals are significantly associated with these three types of pathophysiological status. In order to examine their diagnostic ability, 289 serum samples from 124 MTC patients, 43 BTT patients, and 122 normal controls were randomly divided into the training set and validation set. A biomarker of PC(34:1) exhibited excellent diagnostic ability to differentiate both MTC and BTT patients from normal individuals, with an area under the receiver operating characteristic (ROC) curve value of 0.984, a sensitivity of 96.4 %, and a specificity of 92.7 %. A panel which included PA(36:3) and SM(34:1) could distinguish between MTC and BTT, with an area under receiver operating characteristic curve (AUC) of 0.961, a sensitivity of 87.8 %, and a specificity of 92.9 %. It is worth noting that a panel consisting of PC(34:1), PA(36:3), and SM(34:1) could differentiate MTC patients from both BTT patients and normal individuals, with an AUC of 0.841, a sensitivity of 86.6 %, and a specificity of 75.5 %.