Cyclization of Nitrospirobenzopyrans to Bridged Benzoxazepino[3,2-a]indoles

Condensation of 1-substituted 1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-ones with 5-nitrosalicylaldehyde afforded 1′-[(N-monosubstituted carbamoyl)methyl]indoline nitrospirobenzopyrans. Treatment of the latter with strong base led to the formation of a mixture of cis/trans-5a,13-methano-1,3-benzoxazepino[3,2-a]indoles. Results of semiempirical calculations gave evidence that such a transformation of nitrospirobenzopyrans to bicyclic indole derivatives could proceed via a single transition state, where the negatively charged carbon atom attacks the vinylic double bond of the spiropyran system.     

Design and characterization of flow-through coulometric cells with porous working electrodes made of crushed vitreous carbon

Summary Three types of flow-through, three-electrode cells with porous working electrodes made of crushed vitreous carbon were tested. The electrochemical properties of the cells were studied by hydrodynamic and cyclic voltammetry using potassium ferrocyanide test solutions. Depending on the volume of the porous working electrode, Nernstian behaviour and electrochemical yields up to 100% were observed for flow rates 1 to 7 ml/min. In the stopped-flow regime the cells exhibit thin-layer cell properties. The utility of the cells is demonstrated for on-line coulometric detection, continuous removal of impurities and dissolved oxygen and for anodic stripping coulometry of trace copper.On leave from: Department of Analytical Chemistry, Slovak Technical University, CS-812 37 Bratislava, Czechoslovakia     

Human topoisomerase I poisoning: docking protoberberines into a structure-based binding site model

Summary Using the X-ray crystal structure of the human topoisomerase I (top1) – DNA cleavable complex and the Sybyl software package, we have developed a general model for the ternary cleavable complex formed with four protoberberine alkaloids differing in the substitution on the terminal phenyl rings and covering a broad range of the top1-poisoning activities. This model has the drug intercalated with its planar chromophore between the −1 and +1 base pairs flanking the cleavage site, with the nonplanar portion pointing into the minor groove. The ternary complexes were geometry-optimized and relative interaction energies, computed by using the Tripos force field, were found to rank in correct order the biological potency of the compounds; in addition, the model is also consistent with the top1-poisoning inactivity of berberine, a major prototype of the protoberberine alkaloids. The model might serve as a rational basis for elaboration of the most active compound as a lead structure, in order to develop more potent top1 poisons as next generation anti-cancer drugs.     

X-Ray Powder Diffraction Studies of Polyhydrates of Cross-Linked Tetraisoamylammonium Polyacrylates

X-ray powder diffraction studies were performed of the polyhydrates, formed at positive temperature in swelled grains of carboxylic cation-exchange resins in the form of tetraisoamylammonium (cross-linked tetraisoamylammonium polyacrylates, differing in the degree of cross-linking: 1, 2 and 3%). It was shown that the polyhydrates exist as the crystalline phase under specific conditions, determined earlier by DTA technique. Diffraction patterns of the samples, recorded at the temperature +3 ± 1 °C, indicate that the polyhydrates crystallize in hexagonal symmetry, the unit cell parameters are close to a=12.25 Å, c=12.72 Å and do not depend significantly upon the degree of cross-linking. The suppositions were made concerning the size of hydrate crystallites, formed in the swelled grains of the studied resins.This revised version was published online in July 2005 with a corrected issue number.     

An <Emphasis Type="BoldItalic">in silico</Emphasis> approach for screening flavonoids as P-glycoprotein inhibitors based on a Bayesian-regularized neural network

Summary P-glycoprotein (P-gp), an ATP-binding cassette (ABC) transporter, functions as a biological barrier by extruding cytotoxic agents out of cells, resulting in an obstacle in chemotherapeutic treatment of cancer. In order to aid in the development of potential P-gp inhibitors, we constructed a quantitative structure–activity relationship (QSAR) model of flavonoids as P-gp inhibitors based on Bayesian-regularized neural network (BRNN). A dataset of 57 flavonoids collected from a literature binding to the C-terminal nucleotide-binding domain of mouse P-gp was compiled. The predictive ability of the model was assessed using a test set that was independent of the training set, which showed a standard error of prediction of 0.146 ± 0.006 (data scaled from 0 to 1). Meanwhile, two other mathematical tools, back-propagation neural network (BPNN) and partial least squares (PLS) were also attempted to build QSAR models. The BRNN provided slightly better results for the test set compared to BPNN, but the difference was not significant according to F-statistic at p = 0.05. The PLS failed to build a reliable model in the present study. Our study indicates that the BRNN-based in silico model has good potential in facilitating the prediction of P-gp flavonoid inhibitors and might be applied in further drug design.     

Stereoselective discrimination and quantification of arginine and N-blocked arginine enantiomers by formation and dissociation of calcium-mediated diastereomeric trimer complexes with a chiral reference compound using electrospray ionization-ion trap tandem mass spectrometry

Chiral resolution of arginine (Arg) and Arg derivatives is demonstrated using electrospray ionization-tandem mass spectrometry (ESI-MS). Calcium ion (Ca(II))-mediated trimeric clusters are generated, which incorporate the analyte of interest and an enantiomerically pure reference molecule of similar metal ion affinity. Two methods, one based on the measurement of a competitive-dissociation-based branching ratio (R(chir)) by the kinetic method (KM) and one based on the measurement of a chiral recognition ratio (CR) by a similar method, are compared. Incorporating N-blocked Arg derivatives (Z-Arg and Boc-Arg) as chiral references provides chiral resolution greater than that previously reported for Arg enantiomers. In a reciprocal manner, pure Arg enantiomers can be used as references for discriminating enantiomers of these N-blocked Arg derivatives. Condensed-phase and gas-phase Ca(II) ion affinity relative to Arg is also addressed qualitatively for other acidic, basic, and neutral amino acids. In some cases, when only one offspring ion is observed (insufficient for KM analysis), the CR method can be applied as an alternative to obtain a measurable stereoselectivity value for the system. The results of these experiments demonstrate the applicability of, and the difference between, the KM and the CR method for improved quantitative analysis of enantiomeric excess for Arg.     

Microemulsion photopolymerization of methacrylates stabilized with sodium dodecyl sulfate and poly(N-acetylethylenimine) macromonomers

Methyl methacrylate and butyl methacrylate were polymerized in oil-in-water microemulsions that were stabilized by sodium dodecyl sulphate (SDS). A poly(N-acetylethylenimine) (PNAEI) macromer was also included in the recipe, as a cosurfactant and a comonomer. Polymerizations were initiated by UV-irradiation. The average diameters of latex particles, obtained by STM, were in the range of 17-200 nm. The experimental data evidenced that the particle size was mainly dependent on the SDS/PNAEI ratio. Polymerization yields were around 75-85%. The synthesized copolymers have viscosity average molecular weights in the range of 2.1-2.4×10⁶ and glass transition temperatures of 38.0-43.5°C, lower than those obtained without using PNAEI. The investigation by means of FTIR and 1H-NMR techniques revealed that PNAEI was incorporated into the nanoparticles.     

Sonoelectroanalysis: investigation of bismuth-film-modified glassy carbon electrodes

Bismuth-modified glassy carbon electrodes have been investigated for their suitability in sonoelectroanalysis. The stability of the bismuth film to the application of ultrasound was assessed via voltammetric and atomic force microscopy (AFM) studies which revealed little ablation at powers up to an intensity of 130 W cm^–2 delivered from a 25-kHz sonic horn. Furthermore, bismuth-film-modified glassy carbon electrodes were evaluated for the sonoelectroanalytical quantification of zinc and cadmium. Detection limits of 2×10^–7 M and 6×10^–9 M respectively were found after a 60-s deposition time via an acoustically assisted deposition protocol.     

An Efficient Synthesis of <Emphasis Type="Italic">O</Emphasis>-Methyl Protected Emodin Aldehyde and Emodin Nitrile

Summary. An efficient synthesis of tri-O-methylemodin aldehyde was achieved via bromination of tri-O-methylemodin utilizing N-bromosuccinimide yielding the monobromo and dibromo derivatives. Sommelet reaction of the monobromomethyl derivative as well as hydrolysis of the dibromomethyl analog with aqueous silver nitrate afforded the protected aldehyde in good yield. Accordingly, both bromo derivatives can be used even when they are obtained as a mixture of the bromination reaction, which could not be controlled easily to yield the bromo products selectively. From the aldehyde the tri-O-methylemodin nitrile was prepared in a one-pot reaction using hydroxylamine-O-sulfonic acid.Received February 18, 2003; accepted March 3, 2003 Published online June 2, 2003