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The synthesis of eight fluorene-9-spiro-2'-(N-aryl-3' ,3'-dichloroaziridines) was achieved via the reaction of dichlorocarbene with the appropriately substituted N-fluorenylideneanilines. Hydrolysis of the spirofluorenes afforded the corresponding 9-chlorofluorene-9-carboxanilides in excellent yields.
The adsorption of four adsorptiochromic spiropyrans to many solids (silica gel, silicic acid, fumed silica, alumina, microcrystalline cellulose, talc, titanium dioxide) was studied at 25 degrees C from cyclohexane solution. Nineteen adsorption isotherms were determined; and the binding data were fitted to the Langmuir equation. A model for binding of adsorptiochromic substances is described, and the parameters of the model are related to the experimental binding constant K.
The colored powders produced by the adsorption of four adsorptiochromic spiropyrans to many solids (silica gel, silicic acid, fumed silica, alumina, microcrystalline cellulose, talc, titanium dioxide) were examined by diffuse reflectance spectroscopy. The reflectance spectra were dominated by two bands, one at 550 nm and the other in the range 400-500 nm, often at 472 nm. Plots of the Kubelka-Munk function [F(R' infinity)] against g, the coverage expressed in nmol/m2, were linear at very low g and approached a limiting value independent of g at high coverage. The color formation upon adsorption terminates at coverages much lower than the maximum binding capacity of the solid. The slope of the plot of F(R' infinity) against g, at low g (denoted f0), appears to be sensitive to the scattering properties of the solid. For a single solid (silica gel), comparison of f0 for adsorptiochromic adsorbates with f0 for permanent dyes allowed estimates to be made of the fraction of adsorbed spiropyran in the colored form on the surface.
The pharmacokinetics of two spiroarsorane molecules (1,2) were investigated after both intravenous bolus and an oral administration in rabbits. After iv administration of a 15-mg/kg dose, for the two substances, the plasma concentration-time curves were well described by an open two-compartmental model. The half-lives of the first phase were 0.47 +/- 0.12 and 0.27 +/- 0.02 h for 1 and 2, respectively. The half-lives of the terminal phase were of the same order of magnitude for the two substances: 4.38 +/- 0.24 and 6.03 +/- 1.14 h, respectively. Total plasma clearances were 2.47 +/- 0.44 and 0.81 +/- 0.04 L/h, respectively, and the steady-state volume of distribution of 2 (14.99 +/- 2.57 L) was larger than that of 1 (4.27 +/- 0.28 L). After oral administration, spiroarsorane 2 was not absorbed. The availability of the suspension of 1 was 18%. The rate of the absorption phase of 1 showed a saturation process, probably due to the solubility of the molecule. When increasing oral doses of 1 (15, 30, and 60 mg/kg) were administered, the plasma concentrations did not increase to the same extent.
Carbon-carbon spin-spin coupling constants were calculated at the SOPPA level for a series of seven classical spiroalkanes, spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane, spiro[3.3]heptane, spiro[4.4]nonane and spiro[5.5]undecane, with special focus upon couplings involving and/or across spiro carbons. Many interesting structural trends were investigated originating in specific geometries and unusual bonding environments at the spiro carbon.
Extracts of roots Phyllanthus acidus were examined by free zone capillary electrophoresis, micellar electrokinetic chromatography (MEKC), and MEKC using the sweeping technique which involves application of a negative potential to the inlet end of the capillary and very much longer than conventional injection times. The latter technique, using a buffer of 50 mM sodium dihydrogen phosphate (pH 2) containing 80 mM sodium dodecylsulphate and 30% methanol was found to allow complete resolution of the active constituents of P. acidus, phyllanthusols A and B, from each other and from other extracted components in under 30 min. Several other components could be detected when hydrodynamic injection times of 500 s were used. The separation, combined with an appropriate extraction procedure and using an internal standard of proguanil, permitted quantification of both phyllanthusols. Calibrations were linear over the range 2-8 micrograms/mL for phyllanthusol A, and 1-4 micrograms/mL for phyllanthusol B. Within-day and day-to-day repeatability RSDs were below 10%, and the precision of extraction RSD was around 14%. The limits of quantification and detection were 0.55 and 0.24 microgram/mL, respectively.
This paper describes the syntheses and biological activities of a number of spiroketal enol ethers which are analogues of the plant extract tonghaosu. The insecticidal potential of this spiroketal system is assessed.
Plumieride has been isolated as an active principle of the leaves of Allamanda cathartica. It showed strong fungitoxicity against some dermatophytes causing dermatomycosis to animals and human beings. It exhibited a noncytotoxic nature against a P(388) mouse leukaemia cell line.
Azaspiracids are neurotoxins produced by marine algae that have been detected in harvested mussels since 1995. They pose a significant threat to human health through the consumption of contaminated shellfish, and negatively impact the economy of areas where shellfish are harvested and processed. Regulatory agencies are beginning to advocate instrumental assays over traditional mouse bioassay methods. The development and validation of an assay method for AZA 1, the predominant azaspiracid toxin, and the production of a calibration standard and reference material will therefore be vital for quality control in monitoring laboratories worldwide. This report demonstrates a rapid and reproducible liquid chromatography/mass spectrometry (LC/MS) method for separation of all twelve known azaspiracids. Using a triple-quadrupole mass spectrometer, ultra-high sensitivity was obtained at the low-femtogram level injected on-column. At the same time, a linear response of three orders of magnitude was observed. We compared the results with those measured on an ion-trap mass spectrometer. The triple-quadrupole instrument was more sensitive, reliable and reproducible than the ion-trap instrument. The detection limit obtained on the ion-trap mass spectrometer was ten times higher than that obtained on the triple quadrupole. During the study, a new azaspiracid analog (AZA 7c) was discovered.
The fragmentation patterns of a series of dispirocyclopiperazinium dibromides with strong analgesic activity are analyzed by positive ion electrospray ionization mass spectrometry in conjunction with tandem mass spectrometry (ESI-MS(n)). Instead of the parent molecular ions, the fragment ions [M-Br](+) are detected as characteristic double peaks and usually the base peaks. Meanwhile, the fragment ions [M-2Br](2+) are unique for this series of diquaternary ammonium dibromides and show high intensity. Besides the common fragmentation patterns around the carbonyl group, elimination of hydrogen bromide from [M--Br](+) ions is another important pathway. Following the elimination, an interesting rearrangement takes place in the unsaturated spirocyclopiperazine and transforms it into a dihydropyrrole structure, whose fragmentations are similar to its precursor ion in the succeeding steps.
Azaspiracid (AZA1), a recently discovered marine toxin, is responsible for the new human toxic syndrome, azaspiracid poisoning (AZP), which is caused by the consumption of contaminated shellfish. A new, sensitive liquid chromatography/mass spectrometry (LC/MS) method has been developed for the determination of AZA1 and its analogues, 8-methylazaspiracid (AZA2) and 22-demethylazaspiracid (AZA3). Separation of these toxins was achieved using reversed-phase LC and coupled, via an electrospray ionisation (ESI) source, to an ion-trap mass spectrometer. Spectra showed the protonated molecules, [M + H]+, and their major product ions, due to the sequential loss of two water molecules, [M + H - H2O]+, [M + H - 2H2O]+, in addition to fragment ions that are characteristic of these cyclic polyethers. A highly specific and sensitive LC/MS(3) analytical method was developed and, using shellfish extracts containing AZA1, the detection limit (S/N = 3) was 4 pg on-column, corresponding to 0.8 ng/mL. Using the protocol presented here, this is equivalent to 0.37 ng/g shellfish tissue and good linear calibrations were obtained for AZA1 in shellfish extracts (average r2 = 0.9988). Good reproducibility was achieved with % RSD values (N = 5) ranging from 1.5% (0.75 microg/mL) to 4.2% (0.05 microg/mL). An efficient procedure for the extraction of toxins from shellfish aided the development of a rapid protocol for the determination of the three predominant azaspiracids.
In this study, the performance of monolithic columns was evaluated for ultrafast liquid chromatography/mass spectrometry (LC/MS) analyses and for high-resolution separations of several azaspiracid biotoxin analogs. Because of their high permeability, monolithic columns offer a number of advantages over conventional packed columns; viz., very low backpressures and relatively flat van Deemter curves at high flow rates. That is, very high flow rates can be used for ultrafast analyses or, by using longer than normal columns, high-resolution separations are possible. In a series of experiments, we varied the mobile phase flow rates between 1 and 8 mL/min, and studied their impact on chromatographic parameters such as retention time, resolution, number of plates and pressure. The chromatographic run times could be reduced to ca. 30 s without a significant change in the separation efficiency. A signal intensity comparison revealed interesting differences between atmospheric-pressure chemical ionization (APCI) and electrospray ionization (ESI) in their flow-rate dependency. An explanation with respect to the behavior as of a mass-flow or a concentration-dependent device is given in the paper. Additionally, the column length was varied between 10 and 70 cm. As a result, the number of theoretical plates increased substantially. In the example shown in the report, an increase from 13 000 plates for a 10-cm column to 80 000 for a 70-cm column is demonstrated. In addition, the potential of the monolithic columns for high-resolution LC/MS separations is shown for a complex biotoxin mixture, which was separated on a 40-cm-long column.
Nitroxides stable radicals are unreactive toward most diamagnetic molecules, but readily undergo one-electron redox reactions with paramagnetic species such as free radicals and transition metals, thus serving as cell-permeable antioxidants. The cytotoxicity of juglone (5-hydroxy-1,4-naphthoquinone), like that of other naphthoquinones, requires bioreduction to yield the semiquinone which in turn reduces oxygen to O2.-. Therefore, nitroxides are expected to mitigate cytotoxicity of quinone-based xenobiotics, such as naphthoquinones. In the present study, in vitro scission of isolated DNA was induced upon juglone reduction by glutathione and Fe(II) ions, however, not by xanthine oxidase or cytochrome c reductase. The DNA scission was inhibited by nitroxides, catalase and chelating agents, though not by superoxide dismutase. Juglone was more toxic toward bacterial cells under hypoxia than under air. Nitroxides < or = 2 mM protected bacterial cells from juglone-induced toxicity under both aerobic and hypoxic conditions. The cytoprotective effect of lipophilic nitroxide was greater than that of hydrophilic ones. Catalase and metal chelating agents decreased juglone-induced cell killing, whereas H2O2 increased it. The mechanisms underlying the nitroxides protective effect involve (a) the reoxidation of reduced transition metal ions, (b) the selective radical-radical reaction with juglone semiquinone, and possibly (c) under aerobic condition catalytic removal of extra- and intracellular O2.-. The present results suggest also that the cell membrane rather than DNA is the main target of juglone toxicity.
Human immunodeficiency virus type 1 (HIV-1) recombinant reverse transcriptase (RT) containing lysine (Lys) instead of glutamic acid (Glu) at position 138 proved fully resistant to the inhibitory effect of TSAO derivatives, but retained marked sensitivity to all other HIV-1-specific inhibitors investigated. In contrast, 181 Tyr-->Cys mutated RT lost sensitivity to all HIV-1-specific inhibitors. There was a close correlation between the sensitivity/resistance pattern of HIV-1-specific inhibitors against mutated (138 Glu-->Lys) recombinant HIV-1 RT and mutant virus strains selected for resistance against TSAO-m3T in cell culture and proven to contain the 138-Lys mutation as the sole mutation within the amino acid 50-270 region of their RT.
Lactacystin (1.3 microM), a metabolite from an actinomycete, induced the formation of bipolar projections at both sides of the cell body of Neuro 2a cells 1 day after treatment and networks at and after 3 days and enhanced acetylcholinesterase activity (a marker of neuronal differentiation). Thus, the neuronal differentiation was characterized both morphologically and functionally. The experiments with various inhibitors of protein kinases and phosphatases revealed that the protein phosphatase inhibitors calyculin A (0.5 nM) and okadaic acid (0.6 nM) inhibit the formation of bipolar projections at 1 day, but does not inhibit the network formation at and after 3 days.
Bistratene A (BisA) induced growth arrest in G2/M in HL60 cells. In addition, BisA-treated cells (50 nM for 48 h) became adherent and expressed the adhesion molecule CD11c, but did not express the monocyte enzyme alpha-napthyl acetate esterase or phagocytose complement coated yeasts. BisA activated protein kinase C (PKC)-delta and induced translocation of PKC-delta to the nucleus. This suggests that activation of PKC-delta can induce growth arrest and cell adhesion, but is insufficient to mediate full differentiation of HL60 cells. BisA has potential as a new probe for determining the function of PKC isoenzymes, specifically PKC-delta.
The present work was undertaken to test whether cytoskeletal components are involved in the control of rat-liver carnitine palmitoyltransferase I (CPT-I) activity by cellular effectors. The microtubule stabilizer taxol abolished the changes in CPT-I activity induced by the effectors tested. Taxol also prevented OA-induced shrinkage of hepatocytes as well as the enhanced release of lactate dehydrogenase from digitonin-permeabilized hepatocytes. On the basis of its relative sensitivity to tautomycin and OA, the modulation of CPT-I activity seemed to involve mostly protein phosphatase 1. These data suggest that the short-term control of hepatic CPT-I by cellular effectors may involve modulation of interactions between CPT-I and cytoskeletal components.
The discovery of a potential new GH therapy by small molecules that induce GH secretion (GHRP-6, L-692,429, MK-0677), has increased the interest in these GH secretagogues and their receptor and mechanism of action, which is different from the one of GHRH. We report the solubilization of the GH-secretagogue-receptor-ligand-G-protein complex (apparent molecular mass of approximately 255 kDa) from porcine anterior pituitary membranes using digitonin, after labelling the receptor with [35S]MK-0677. The solubilized receptor showed high affinity (KD = 122.2 +/- 14.4 pM) and low capacity (Bmax = 3.8 +/- 0.9 fmol/mg protein). These values and the inhibition constants (Ki) for a series of GH secretagogues were similar to the values determined in membranes isolated from porcine anterior pituitary gland. The solubilization of the GH secretagogue receptor opens up the possibility for further molecular characterization and sequencing of the receptor protein, necessary step prior to the identification of the natural ligand that would act as a GHRH amplifying hormone, and that the GH secretagogues would mimic.