A convenient synthesis of a selective gelatinase inhibitor as an antimetastatic agent

Compound 1, 2-(4-phenoxyphenylsulfonylmethyl)thiirane, is a potent and selective inhibitor for human gelatinases (J. Am. Chem. Soc. 2000, 122, 6799-6800), enzymes implicated in a number of diseases, including cancer. This compound is showing excellent promise in animal trials in a number of disease models. Large quantities of this compound were necessary for these studies. A convenient four-step synthetic route for compound 1 is described herein. The synthesis is amenable to scale-up to tens of grams and gives an overall yield of 57% for this important compound.     

Determination of Dextromethorphan and its Metabolite Dextrorphan in Human Hair by Gas Chromatography–Mass Spectrometry

An analytical method has been developed for determination of dextromethorphan (DMP) and dextrorphan (DRP) in human hair by gas chromatography–mass spectrometry (GC–MS). Hair samples (30 mg) were washed with distilled water and acetone and cut into small fragments (<1 mm) before extraction with methanol. The extracts were evaporated to dryness and then derivatized by use of BSTFA containing 1% TMCS, for preparation of the trimethylsilyl (TMS) derivative of DRP. The extract (1 μL) was then injected into the GC–MS. Recoveries of DMP and DRP at 7.0 and 22.5 ng mg^?1 were in the range 90.6–97.2% with intra-assay and inter-assay precision of less than 5.7% and 4.7%, respectively. LOD and LOQ were, respectively, 0.67 and 2.13 ng mg^?1 for DMP and 0.14 and 0.47 ng mg^?1 for DRP. The responses were linear with correlation coefficients (r > 0.9995) for the drugs studied. The applicability of the method was proven by analysis of authentic hair samples.     

Simultaneous determination of N-butylscopolamine and oxazepam in pharmaceutical formulations by first-order digital derivative spectrophotometry

A simple method has been developed for the simultaneous determination of N-butylscopolamine bromide and oxazepam in pharmaceutical formulations using first-order digital derivative spectrophotometry. Acetonitrile was selected as the solvent in which both compounds showed well-defined bands. Both analytes showed good stability in this solvent when solutions of the analytes were exposed to light and temperatures between 20 degrees and 80 degrees C. The simultaneous determination of both drugs was performed by the zero-crossing method at 226.0 and 257.0 nm for N-butylscopolamine and oxazepam, respectively. The linear range of determination was found to be 2.5 x 10(-7) to 8.0 x 10(-5) mol/L for N-butylscopolamine and 7.1 x 10(-8) to 8.0 x 10(-5) mol/L for oxazepam. A very good level of repeatability (relative standard deviation) of 0.2% was observed for N-butylscopolamine and oxazepam. The ingredients commonly found in pharmaceutical formulations do not interfere. The proposed method was applied to the determination of these drugs in pharmaceutical formulations (capsules).     

Synthesis of non-agglomerated Ba<Subscript>0.77</Subscript>Ca<Subscript>0.23</Subscript>TiO<Subscript>3</Subscript> nanopowders by a modified polymeric precursor method

In this work, we have studied the influence of the pH on the synthesis and structural properties of the Ba_0.77Ca_0.23TiO₃ nanopowders synthesized by a modified polymeric precursor method, in order to achieve non-agglomerated powders. Synthesis, morphology, thermal reactions, crystallite and average particle size of the synthesized powders were investigated through thermal analysis (DTA/TG), X-ray diffraction (XRD), field emission scanning electron microscope (FE-SEM) and Infrared spectroscopy. In summary, Ba_0.77Ca_0.23TiO₃ nanopowders were synthesized for the first time at a relative low temperature (500 °C). It was also found that the alkalinity and acidity of the solution presented a great influence on the powder properties. The best results were obtained from solutions with pH = 8.5 and 11 whose nanopowders presented weakly agglomerate, with homogeneous particle size and a narrow size distribution (30–40 nm). This behavior could be explained based on the FT-IR results in which it was possible to see the increased of the chelation in higher pHs.     

Large-volume stacking in capillary electrophoresis using pH hysteresis of the electroosmotic flow in a bare fused-silica capillary

For large-volume stacking with the electroosmotic flow pump (LVSEP) in capillary electrophoresis of anionic analytes it is required that the electroosmotic mobility (EOM) should be smaller than the magnitudes of the effective mobilities of the analytes. When a fused-silica capillary is treated with an acidic solution, the silanoate group on the silica surface is neutralized to silanol and the EOM is suppressed. Due to the slow deprotonation equilibrium of the silanol group at an intermediate pH, this reduced EOM can be retained during a number of electrophoresis runs. Using a bare fused-silica capillary preconditioned with 0.01 M HCl, successful LVSEP at pH 6.0 was achieved for weakly acidic compounds with two orders of magnitude enhancements in the concentration sensitivity. The repeatability in migration times of ten analytes stacked by LVSEP in a single day was excellent with the relative standard deviation (RSD) less than 1% (n = 6). The day-to-day repeatability was also excellent with RSD less than 3% (n = 3 x 6) when the capillary was preconditioned each day.     

Structural determination of hexadecanoic lysophosphatidylcholine regioisomers by fast atom bombardment tandem mass spectrometry

The structural determination of sn-1 and sn-2 hexadecanoic lysophosphatidylcholine (LPC) regioisomers was carried out using fast atom bombardment tandem mass spectrometry (FAB-MS/MS). The collision-induced dissociation (CID) of protonated and sodiated molecules produced diverse product ions due mainly to charge remote fragmentations. Based on the information obtained from the CID spectra of protonated and sodiated molecules, sn-1 and sn-2 hexadecanoic LPC isomers could be discriminated. Especially, the abundance ratio of the diagnostic ion pair [m/z 224/226] in the CID spectra of [M + H](+) ions was shown to be greatly different. Moreover, the CID-MS/MS spectra of sodium-adducted molecules for hexadecanoic LPC isomers showed characteristic product ions such as [M + Na - 103](+), [M + Na - 85](+), and [M + Na - 59](+), by which their regio-specificity can be differentiated.     

ZIP8 exacerbates collagen-induced arthritis by increasing pathogenic T cell responses

Zinc is a trace element that is essential for immune responses. Therefore, changes in cellular zinc levels in specific immune cells may influence inflammatory autoimmune diseases, such as rheumatoid arthritis (RA). However, the regulation of zinc mobilization in immune cells and its role in the pathogenesis of RA are not fully understood. Thus, we investigated the roles of zinc transporters in RA pathogenesis. We demonstrated that ZIP8 was specifically upregulated in CD4⁺ T cells that infiltrated the inflamed joint and that ZIP8 deficiency in CD4⁺ T cells abrogated collagen-induced arthritis. ZIP8 deficiency dramatically affected zinc influx in effector T cells and profoundly reduced T cell receptor (TCR)-mediated signaling, including NF-κB and MAPK signaling, which are pathways that are involved in T helper (Th) 17 cell differentiation. Taken together, our findings suggest that ZIP8 depletion in CD4⁺ T cells attenuates TCR signaling due to insufficient cellular zinc, thereby reducing the function of effector CD4⁺ T cells, including Th17 cells. Our results also suggest that targeting ZIP8 may be a useful strategy to inhibit RA development and pathogenesis.Subject terms: Autoimmunity, Immunological disorders     

A novel and efficient approach to highly substituted indolizines via 5-endo-trig iodocyclization

A new approach to indolizines has been developed using a 5-endo-trig iodocyclization of allylic esters followed by isomerization and dehydroiodination facilitated by triethylamine at rt. This mild procedure enabled us to synthesize a number of highly substituted indolizines in good yields.     

All-solid-state carbonate-selective electrode based on a molecular tweezer-type neutral carrier with solvent-soluble conducting polymer solid contact

Carbonate-selective membranes were prepared by incorporating a molecular tweezer-type carbonate-selective neutral carrier [N,N-dioctyl-3alpha,12alpha-bis(4-trifluoroacetylbenzyloxy)-5beta-cholan-24-amide] into a room temperature vulcanizing-type silicone rubber (3140 RTV-SR) matrix, and deposited on the planar-type electrodes (Pt containing Ag/AgCl electrodes formed on a ceramic plate) with and without an intermediary conducting polymer layer. Two types of solvent-soluble conducting polymers [poly(1-hexyl-3,4-dimethyl-2,5-pyrrolylene) or poly(3-octylthiophene-2,5-diyl)] have been examined as the solid contact material. Potentiometric properties of the resultant all-solid-state electrodes were evaluated in terms of their carbonate selectivity, response slope, potential stability and reproducibility. The sensitivity and carbonate selectivity of the SR membrane-based all-solid-state electrodes with conducting polymer solid contact were comparable to those of conventional electrodes. Experimental results also showed that the intermediary conducting polymer layer used in the all-solid-state electrodes greatly reduces the interference from dissolved oxygen.