Synthesis of polyhydroxy piperidines and their analogues: a novel approach towards selective inhibitors of alpha-glucosidase

Various polyhydroxy piperidine azasugars have been synthesized from precursors 18a and 18b, obtained in both enantiomeric forms from d-ribose. Out of these polyhydroxy piperidine azasugars, 22, 39 and 20 were found to be potent as well as selective inhibitors of alpha-glucosidase with K(i) values ranging as low as 1.07 microM, 16.4 microM, and 88.2 microM, respectively. Replacement of the hydroxy methylene moiety of (K(i) 33% at 1 mM) by an amino methylene moiety (32, K(i) 36.8 microM) showed a remarkable increase in the activity (almost 30 times). Furthermore, increasing the lipophilicity of by N-alkylation with a dodecyl group (36) showed a three-fold enhancement in the activity (K(i) 217 microM to K(i) 72.3 microM).     

Shear-induced crystallization in phase-separated blends of isotactic polypropylene with ethylene-propylene-diene terpolymer

The compatibility between isotactic polypropylene(i PP) and ethylene-propylene-diene terpolymer(EPDM) in the blends was studied. SAXS analysis indicates that i PP and EPDM phases in the binary blend are incompatible. Isothermal crystallization behaviors of i PP in phase-separated i PP/EPDM were studied by in situ POM equipped with a Linkam shear hot stage. It was found that typical spherulites of i PP were formed both in neat i PP and in i PP/EPDM blends. The radial growth rate(d R/dt) of spherulites of i PP in the blend was not influenced by EPDM phases. Further investigations on isothermal crystallization of i PP in i PP/EPDM after shear with a fixed shear time showed that the crystallization rate of i PP in the blends increased with increasing shear rates, whereas, the crystallization rate was much lower than that of neat i PP. WAXD results showed that ?-crystal i PP was formed in neat i PP as well as in i PP/EPDM blends after shearing and the percentage of ?-crystal bore a relationship to the applied shear rate. The presence of EPDM resulted in lower percentage of ?-crystal in the blends than that in neat i PP under the same constant shear conditions. SAXS experiments revealed that shear flow could induce formation of oriented lamellae in i PP and i PP in the blends, and the presence of EPDM led to a reduced fraction of oriented lamellae.     

Comparative pharmacokinetics of 67Ga among the different routes of injection

The pharmacokinetic study of 67Ga-citrate (67Ga) following intravenous (i.v.), subcutaneous (s.c.) and intraperitoneal (i.p.) injection was performed in anesthetized rats using the repeated blood sampling method by cannulation technique into the external jugular vein. The disappearance of 67Ga from the blood following i.v. and s.c. injection was best fit a three-exponential equation. There was no significant difference between the areas under the curves following i.v. and s.c. injection of 67Ga. In the case of i.p. injection, the disappearance of 67Ga from the blood was described by a two-exponential equation. However, the maximum blood radioactivity was very low, and the disappearance rate of 67Ga from the blood was extremely slow compared to the other routes of injection. The conclusion from these results was that s.c. injection was as suitable as i.v. injection, but i.p. injection was not appropriate for the distribution study of 67Ga such as scintigraphy or autoradiography. However, i.p. route may be available for a special experiment which needs the long-time retention of 67Ga in the blood.     

Experimental and theoretical investigations of the redox behavior of the heterodichalcogenido ligands [(EP(i)Pr2)(TeP(i)Pr2)N](-) (E = S, Se): cyclic cations and acyclic dichalcogenide dimers

The two-electron oxidation of the lithium salts of the heterodichalcogenidoimidodiphosphinate anions [(EP (i)Pr 2)(TeP (i)Pr 2)N] (-) ( 1a, E = S; 1b, E = Se) with iodine yields cyclic cations [(EP (i)Pr 2)(TeP (i)Pr 2)N] (+) as their iodide salts [(SP (i)Pr 2)(TeP (i)Pr 2)N]I ( 2a) and [(SeP (i)Pr 2)(TeP (i)Pr 2)N]I ( 2b). The five-membered rings in 2a and 2b both display an elongated E-Te bond as a consequence of an interaction between tellurium and the iodide anion. One-electron reduction of 2a and 2b with cobaltocene produces the neutral dimers (EP (i)Pr 2NP (i)Pr 2Te-) 2 ( 3a, E = S; 3b, E = Se), which are connected exclusively through a Te-Te bond. Two-electron reduction of 2a and 2b with 2 equiv of cobaltocene regenerates the corresponding dichalcogenidoimidodiphosphinate anions as ion-separated cobaltocenium salts Cp 2Co[(EP (i)Pr 2)(TeP (i)Pr 2)N] ( 4a, E = S; 4b, E = Se). The ditellurido analogue Cp 2Co[(TeP (i)Pr 2) 2N] ( 4c) has been prepared in the same manner for comparison. Density functional theory calculations reveal that the preferential interaction of the iodide anion with tellurium is determined by the polarization of the lowest unoccupied molecular orbital [sigma*(E-Te)] of the cations in 2a and 2b toward tellurium and that the formation of the dimers 3a and 3b with a central Te-Te linkage is energetically more favorable than the structural isomers with either E-Te or E-E bonds. Compounds 2a, 2b, 3a, 3b, 4a, 4b, and 4c have been characterized in solution by multinuclear NMR spectroscopy and in the solid state by X-ray crystallography.     

Electron dynamics in charge-transfer-to-solvent states of aqueous chloride revealed by Cl- 2p resonant Auger-electron spectroscopy

Charge-transfer-to-solvent (CTTS) excited states of aqueous chloride are studied by a novel experimental approach based on resonant inner-shell photoexcitation, Cl(-)aq 2p --> e(i), i = 1-4, which denotes a series of excitations to lowest and higher CTTS states. These states are clearly identified through the occurrence of characteristic spectator Auger decays to double Cl 3p valence-hole states, where the CTTS states can be more stabilized as compared to single Cl(-)aq 2p core excitations and optical valence excitations. Furthermore, we have found for the first time that the CTTS electron e(i) bound by a single Cl 2p hole not only behaves as a spectator e(i) --> e'(i), bound by a double valence-hole state before relaxation of the excited electron (i) itself, but also shows electron dynamics to the relaxed lowest state, e(i) --> e'(1*). This interpretation is supported by ab initio calculations. The key to performing photoelectron and Auger-electron spectroscopy studies from aqueous solutions is the use of a liquid microjet in ultrahigh vacuum in conjunction with synchrotron radiation.     

Synthesis and conformational studies of a beta-turn mimetic incorporated in Leu-enkephalin

A beta-turn mimetic in which the four amino acids of a beta-turn have been replaced by a 10-membered ring has been designed, synthesized, and subjected to conformational studies. In the mimetic, the intramolecular CO(i)-HN(i)(+3) hydrogen bond that is often found in beta-turns has been replaced by an ethylene bridge. In addition, the amide bond between residues i and i + 1 was exchanged for a methylene ether isoster. Such a beta-turn mimetic, based on the first four residues of Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu), was prepared in 15 steps. The synthesis relied on a beta-azido alcohol prepared in five steps from Cbz-Tyr(tBu)-OH as a key, i-position building block. tert-Butyl bromoacetate, glycine, and a Phe-Leu dipetide were then used as building blocks for positions i + 1, i + 2, and i + 3, respectively. Conformational studies based on (1)H NMR data showed that the beta-turn mimetic was flexible, but that it resembled a type-II beta-turn at low temperature. This low energy conformer closely resembled the structure determined for crystalline Leu-enkephalin.     

Entropy considerations in kinetic method experiments

In extended kinetic method experiments, relative binding enthalpies ('affinities') and relative entropies are obtained based on unimolecular dissociation kinetics. A series of ion-bound dimers A-X-B(i) is formed, in which the sample (A) and structurally similar reference molecules (B(i)) are bridged by a central cation or anion (X). The branching ratios of the A-X-B(i) set to A-X and B(i)-X are determined at different internal energies, usually by subjecting A-X-B(i) to collisionally activated dissociation at various collision energies. The dependence of the natural logarithm of the branching ratios on the corresponding B(i)-X bond enthalpies (X affinities of B(i)) is evaluated as a function of internal energy to thereby deduce the A-X bond enthalpy (X affinity of A) as well as an apparent relative entropy of the competitive dissociation channels, Delta(DeltaS(app)). Experiments with proton- and Na(+)-bound dimers show that this approach can yield accurate binding enthalpies. In contrast, the derived Delta(DeltaS(app)) values do not correlate with the corresponding thermodynamic entropy differences between the channels leading to A-X and B(i)-X, even after scaling. The observed trends are reconciled by the transition state switching model. According to this model, the kinetics of barrierless dissociations, such as those encountered in kinetic method studies, are dominated by a family of tight transition states ('entropy bottlenecks') lying lower in energy than the corresponding dissociation thresholds. In general, the relative energies of these tight transition states approximately match those of the dissociation products, but their relative entropies tend to be much smaller, as observed experimentally.     

Pharmacokinetics of caffeine and its metabolites in horses after intravenous, intramuscular or oral administration.

The pharmacokinetics of caffeine (CAF) and its metabolites, dimethylxanthines, were examined in horses administered 2.5 mg/kg of CAF intravenously (i.v.), intramusculary (i.m.), or orally (p.o.). The plasma samples were extracted by Extrelut and the concentrations of CAF and metabolites were determined by high performance liquid chromatography (HPLC) with a short column. The pharmacokinetics of CAF after bolus i.v. injection were described by the assumption of a two-compartment model, and those of CAF after i.m. or p.o. administration were done by the assumption of a one-compartment model. The biologic half lives of CAF were 15.5, 18.6, and 16.4 h after administering i.v., i.m. and p.o., respectively. The extent of the bioavailability of the p.o. administration was determined as 1.04 times the dose. The differences in pharmacokinetic parameters were not statistically significant among administration routes. A straight correlation existed between the logarithms of body weights of different species of animals and those of their biologic half lives of CAF. Therefore, the biologic half life of CAF in an animal might be predictable as a function of its body weight.     

Method for the simultaneous determination of total polyphenol and anthocyan indexes in red wines using a flow injection approach

A simultaneous and fast method for the determination of total polyphenol index (t.p.i.) and total anthocyan index (t.a.i.) has been developed by a flow injection approach and a diode array spectrophotometer for monitoring at 280 and 520 nm, respectively. Linear ranges were obtained from 20 to 70 index units and from 20 to 500 mg l(-1) for the t.p.i. and t.a.i., respectively. The results provided by the proposed method agree with those obtained using the polyphenol index at 280 nm and the Ribereau-Gayon method for the determination of total anthocyans. The sample throughout was 25-30 samples per hour. Analytical features such as repeatability, reproducibility and detection and quantification limits as well as the results of a robustness study based on the Steiner-Younden procedure are also given.     

Secondary ion mass spectra of quaternary pyridine aldoximes

The secondary ion mass spectra (s.i.m.s.) of the most widely used therapeutic monoquaternary pyridine aldoximes and diquaternary pyridine aldoximes, as well as some related monoquaternary ammonium salts and neutral oximes, are reported. The monoquaternary derivatives of the oximes yield prominent intact cations which provide molecular weights, and fragmentation patterns which are dominated by even-electron ions. The diquaternary oximes investigated do not give dications, but rather undergo charge separation reactions sometimes accompanied by intramolecular aromatic substitution, and they sometimes yield monoquaternaries by expulsion of a proton. The s.i. mass spectra are structure-specific for the monoquaternary salts, allowing isomer distinction in the cases examined. Quaternary salts can be quantified by s.i.m.s., and low detection limits (less than 50 ng) are demonstrated here for the oxime salts; thus s.i.m.s. is an appropriate analytical technique for the title compounds. Procedures of derivatization which convert the neutral amines to ionic compounds, such as quaternization with alkyl halides, provide a simple means of obtaining high-quality s.i.m.s.     

Modeling boiling points of cycloalkanes by means of iterated line graph sequences

A class of models for predicting boiling points of cycloalkanes is put forward, based on iterated line graphs L(i), i = 1, 2,., of the molecular graph G = L(0). Let m(i) be the number of edges of L(i), i = 0, 1, 2,. The models analyzed are of the form a(0)m(i)()(0) + a(1)m(i)(1) + a(2)m(i)(2) +. + a(k)m(ik) + b. Our optimal QSPR formulas contain m(0), m(1), m(2), m(3), and/or m(4) but never m(5) and m(6). Their precision is as good as or better than the approximations recently reported by Rücker and Rücker (J. Chem. Inf. Comput. Sci. 1999, 39, 788-802).     

Incorporating beta-turns and a turn mimetic out of context in loop 1 of the WW domain affords cooperatively folded beta-sheets.

To probe the conformational requirements of loop 1 in the Pin1 WW domain, the residues at the i + 2 and i + 3 positions of a beta-turn within this loop were replaced by dPro-Gly and Asn-Gly, which are known to prefer the conformations required at the i + 1 and i + 2 positions of type II' and type I' beta-turns. Conformational specificity or lack thereof was further examined by incorporating into the i + 2 and i + 3 positions a non-alpha-amino acid-based beta-turn mimetic (4-(2'-aminoethyl)-6-dibenzofuran propionic acid residue, 1), which was designed to replace the i + 1 and i + 2 positions of beta-turns. All these Pin WW variants are monomeric and folded as discerned by analytical ultracentrifugation, NMR, and CD. They exhibit cooperative two-state transitions and display thermodynamic stability within 0.5 kcal/mol of the wild-type WW domain, demonstrating that the acquisition of native structure and stability does not require a specific sequence and, by extension, conformation within loop 1. However, it could be that these loop 1 mutations alter the kinetics of antiparallel beta-sheet folding, which will be addressed by subsequent kinetic studies.     

Flow injection analysis. principles,applications and trends

The basic principles of Flow Injection Analysis are outlined. The parameters governing the dispersion of the injected sample zone in the system are discussed, and it is demonstrated how these parameters can be manipulated in order to suit the requirements of an individual analytical procedure. A number of examples illustrating the practical application of f.i.a. are described, comprising the use of automated, stopped-flow, merging-zones, extraction techniques as well as f.i.a. scanning and methods based on intermittent pumping. Updated lists on f.i.a. procedures published and species that can be determined by f.i.a. are included.     

Eu(OPri)3/Tb(OPri)3共掺杂P(MMA-co-St)

Eu(OPri)3/Tb(OPri)3共掺杂P(MMA-co-St);Eu(OPri)3/Tb(OPri)3;共掺杂;P(MMA-co-St);荧光性能     

Fast separations with open tubular ion exchange capillary columns

Fused silica columns of 4.6 μm i.d. were coated with 3-sulfopropylsilane as a cation exchanger and 3-(2-aminoethyl-amino)-propylsilane as an anion exchanger. Fast separations of cations (< 25 seconds) and of anions (< 35 seconds) were obtained, using a potentiometric microelectrode as a detector. In proceeding towards smaller i.d.s, a mixture of alkali metal cations could be separated successfully in an uncoated fused silica capillary of 2.3 μm i.d. as a result of retention by the surface silanol groups at pH 9.4.     

Trends in optical spectrochemical trace analysis with plasma sources

The state-of-art and trends in the development of optical spectrochemical trace analysis with inductively-coupled plasmas (i.c.p.), direct current plasmas (d.c.p.) and microwave-induced plasmas (m.i.p.) are discussed. Innovation in plasma optical emission spectrometry (o.e.s.) is shown ot lie in new sources such as the low-gas-consumption i.c.p., the air and helium i.c.p. as well as the toroidal m.i.p., which is operated at medium power and possibly with moleculary gases. Sample introduction has been improved by using new pneumatic nebulizers, flow injection, electrotheraml vaporization, hydride generation, direct sample insertion and direct solid sampling. Progress in the acquisition of spectral information is attained by high-resolution spectrometry, Fourier-transform spectrometry and by the use of multichannel detectors. D.c.p./o.e.s. is a mature technique for routin work and m.i.p./o.e.s. is a powerful tool for element-specific detection is chromatography. Plasma sources are also suitable atom reservoirs for atomic fluorescence spectrometry and for laser-enhanced ionization spectrometry. Trends in the figures of merit of optical plasma spectrochemical analysis are discussed.     

Strained-cyclophane-induced beta-turn template: design, synthesis, and spectroscopic characterization

[structure: see text] Three tetrapeptides incorporating a 14-membered (R(i+1), S(i+2)) cycloisodityrosine at the i + 1 and i + 2 positions were designed and synthesized. Conformational analysis by (1)H NMR and CD spectra as well as molecular modeling indicated that they all adopt a beta-turn conformation. While the CD spectrum of compound 2 is characteristic of the typical type-II beta-turn (maximum at approximately 200 nm and a minimum at approximately 220 nm), that of 1a (atropisomer of 2) is opposite in sign to the expected spectrum of the type-II beta-turn.     

Catalytic enantioselective allylation of ketoimines

A general catalytic allylation of simple ketoimines was developed using 1 mol % of CuF.3PPh(3) as catalyst, 1.5 mol % of La(O(i)Pr)(3) as the cocatalyst, and stable and nontoxic allylboronic acid pinacol ester as the nucleophile. This reaction constituted a good template for developing the first catalytic enantioselective allylation of ketoimines. In this case, using LiO(i)Pr as the cocatalyst produced higher enantioselectivity and reactivity than La(O(i)Pr)(3). Thus, using the CuF-cyclopentyl-DuPHOS complex (10 mol %) and LiO(i)Pr (30 mol %) in the presence of (t)BuOH (1 equiv) produced high enantioselectivity up to 93% ee from a range of aromatic ketoimines. Mechanistic studies indicated that LiO(i)Pr accelerates the reaction by increasing the concentration of an active nucleophile, allylcopper.     

The influence of sugar synthesis and transport rates on bioenergetics and kinetics of higher plant photosynthesis

We have obtained the theoretical dependences of stromal metabolite steady-state concentrations on external inorganic phosphate (P(i)) concentration. For this purpose, the theoretical model of photosynthesis, earlier described in [Ann. Appl. Biol. 138 (2001) 117], was modified to account for the regulation of starch formation by 3-phosphoglycerate (PGA) to P(i) ratio. When the rate constant of starch synthesis is taken to be independent on PGA/P(i) ratio, the steady-state concentrations of Calvin cycle metabolites and starch were found to change insignificantly as external P(i) concentration increases in wide range. However, as external P(i) range exceeds a critical value, the steady-state concentrations of all metabolites change abruptly. If the rate constant of starch synthesis depends on PGA/P(i) ratio, the steady-state concentrations of stromal metabolites change qualitatively in the same way with the increase of external P(i). However, no abrupt changes of metabolite and starch steady-state levels at high concentration of P(i) are observed. These results testify that the control of starch synthesis by PGA/P(i) ratio makes the photosynthetic system more stable in wide range of external P(i) concentrations.     

The direct inverse method: A novel approach to estimate adsorption isotherm parameters

A novel method to estimate adsorption isotherm parameters is presented and its applicability is studied through synthetic as well as experimental data. This approach assumes a linear dependency of the UV absorption intensity on the solute concentration in the fluid phase, at least in certain ranges of the UV spectra. It was demonstrated that by fitting the absorption profiles, i.e. the new direct inverse method, and by fitting the concentration profiles, i.e. the classical inverse method, very similar adsorption isotherm parameters can be obtained. The findings presented in this work have as important implication the elimination of the requirement of converting a measured absorption intensity into a concentration value, i.e. the elimination of the calibration of the UV signal.