Primary photophysical properties of moxifloxacin--a fluoroquinolone antibiotic

Abstract The photophysical properties of the fluoroquinolone antibiotic moxifloxacin (MOX) were investigated in aqueous media. MOX in water, at pH 7.4, shows two intense absorption bands at 287 and 338 nm (epsilon = 44 000 and 17 000 dm(3) mol(-1) cm(-1), respectively). The absorption and emission properties of MOX are pH-dependent, pK(a) values for the protonation equilibria of both the ground (6.1 and 9.6) and excited singlet states (6.8 and 9.1) of MOX were determined spectroscopically. MOX fluoresces weakly, the quantum yield for fluorescence emission being maximum (0.07) at pH 8. Phosphorescence from the excited triplet state in frozen ethanol solution has a quantum yield of 0.046. Laser flash photolysis and pulse radiolysis studies have been carried out to characterize the transient species of MOX in aqueous solution. On laser excitation, MOX undergoes monophotonic photoionization with a quantum yield of 0.14. This leads to the formation of a long-lived cation radical whose absorption is maximum at 470 nm (epsilon(470) = 3400 dm(3) mol(-1) cm(-1)). The photoionization process releases hydrated electron which rapidly reacts (k = 2.8 x 10(10) dm(3) mol(-1) s(-1)) with ground state MOX, yielding a long-lived anion radical with maximum absorption at 390 nm (epsilon(390) = 2400 dm(3) mol(-1) cm(-1)). The cation radical of MOX is able to oxidize protein components tryptophan and tyrosine. The bimolecular rate constants for these reactions are 2.3 x 10(8) dm(3) mol(-1) s(-1) and 1.3 x 10(8) dm(3) mol(-1) s(-1), respectively. Singlet oxygen sensitized by the MOX triplet state was also detected only in oxygen-saturated D(2)O solutions, with a quantum yield of 0.075.     

Temperature-dependent interconversion of phosphoramidite-Cu complexes detected by combined diffusion studies, 31P NMR, and low-temperature NMR spectroscopy

For copper-catalyzed enantioselective conjugate additions, knowledge about the precatalytic and catalytic complexes has not yet been sufficiently developed to understand the strong influence of different temperatures on these famous reactions. Therefore, NMR experiments with four Cu(I) salts and two phosphoramidite ligands have been performed to elucidate the temperature dependence and the low-temperature structures of these copper complexes. The existence of the precatalytic binuclear complex with a mixed trigonal/tetrahedral coordination on copper is for the first time proven with direct NMR spectroscopic methods. Below 200 K, intermolecular interactions between free ligands and [Cu2X2L3] complexes induce binuclear [Cu2X2L4] complexes similar to the crystal structures. By combining diffusion experiments and (31)P integrals at different temperatures, it is for the first time possible to follow the formation of stoichiometrically different complexes, even under experimental conditions in which the (31)P signals of the complexes are spectroscopically not resolved due to exchange processes. This allows a first correlation between the complex species observed and the synthetic conditions reported. Furthermore, different preferences to build homo- or heterochiral complexes are detected for binaphthol and biphenol phosphoramidite complexes.     

Copper complexes of mono- and ditopic [(methylthio)methyl]borates: missing links and linked systems en route to copper enzyme models

TMEDA-free (TMEDA: tetramethylethylenediamine) LiCH(2)SMe is a suitable reagent for the selective introduction of (methylthio)methyl groups into PhBBr(2) and its p-silylated derivative Me(3)Si--C(6)H(4)--BBr(2). The resulting compounds, R*--C(6)H(4)--B(Br)(CH(2)SMe) (R*=H: 2; R*=SiMe(3): 7) and PhB(CH(2)SMe)(2) (3), form cyclic dimers through B--S adduct bonds in solution and in the solid state. Compounds 2 and 3 have successfully been used for preparing the (N(2)S) scorpionate [PhBpz(2)(CH(2)SMe)](-) ([5](-)) (pz: pyrazol-1-yl) and the (NS(2)) scorpionate [PhBpz(CH(2)SMe)(2)](-), respectively. Compound 7 proved to be an excellent building block for the heteroditopic poly(pyrazol-1-yl)borate p-[pz(3)B--C(6)H(4)--Bpz(2)(CH(2)SMe)](2-) ([10](2-)) that mimics the two ligation sites of the copper enzymes peptidylglycine alpha-hydroxylating monooxygenase and dopamine beta-monooxygenase. Treatment of the monotopic tripod [5](-) with CuCl and CuBr(2) results in the formation of complexes K[Cu(5)(2)] and [Cu(5)(2)]. An X-ray crystallography study of K[Cu(5)(2)] revealed a tetrahedral (N(2)S(2)) coordination environment for the Cu(I) ion, whereas the Cu(II) ion of [Cu(5)(2)] possesses a square-pyramidal (N(4)S) ligand sphere (S-atom in the axial position). The remarkable redox properties of K[Cu(5)(2)] and [Cu(5)(2)] have been assessed by cyclic voltammetry and quantum chemical calculations. The reaction of K[Cu(5)(2)] with dry air leads to the Cu(II) species [Cu(5)(2)] and to a tetranuclear Cu(II) complex featuring [PhB(O)pz(2)](2-) ligands. Addition of CuCl to K(2)[10] gives the complex K(3)[Cu(10)(2)] containing two ligand molecules per Cu(I) center. The Cu(I) ion binds to both heteroscorpionate moieties and thereby establishes a coordination environment similar to that of the Cu(I) ion in K[Cu(5)(2)].     

Isotope dilution quantification of ultratrace gamma-glutamyl-Se-methylselenocysteine species using HPLC with enhanced ICP–MS detection by ultrasonic nebulisation or carbon-loaded plasma

A method for the accurate determination of ultratrace selenium species of relevance to cancer research, such as gamma-glutamyl-Se-methylselenocysteine (γ-glutamyl-SeMC), using species-specific double isotope dilution analysis (IDA) with HPLC–ICP–MS is reported for the first time. The ⁷⁷Se-enriched γ-glutamyl-SeMC spike was produced in-house by collecting the fraction at the retention time of the γ-glutamyl-SeMC peak from a chromatographed aqueous extract of ⁷⁷Se-enriched yeast, pooling the collected fractions and freeze-drying the homogenate. The Se content of this spike was characterised using reverse isotope dilution mass spectrometry (IDMS) and the isotopic composition of this spike was checked prior to quantification of the natural abundance dipeptide species in garlic using speciated IDA. The extraction of the γ-glutamyl-SeMC species in water was performed in a sonication bath for 2 h after adding an appropriate quantity of ⁷⁷Se-enriched γ-glutamyl-SeMC to 50 mg of garlic to give optimal ⁷⁸Se/⁷⁷Se and ⁸²Se/⁷⁷Se ratios of 1.5 and 0.6, respectively. The effect of ultrasonic nebulisation, in comparison with the loading of the ICP with carbon (through the addition of methane gas on-line), on the detection of Se associated with γ-glutamyl-SeMC using collision/reaction cell ICP–MS with hydrogen as collision gas was investigated. Sensitivity enhancements of approximately fourfold and twofold were achieved using USN and methane mixed plasma, respectively, in comparison with conventional nebulisation and conventional Ar ICP–MS. However, an approximately twofold improvement in the detection limit was achieved using both approaches (42 ng kg⁻¹ for ⁷⁸Se using peak height measurements). The use of species-specific IDMS enabled quantification of the dipeptide species at ng g⁻¹ levels (603 ng g⁻¹ Se) in the complex food matrix with a relative standard deviation (RSD, n = 4) of 4.5%, which was approximately half that obtained using standard addition as a confirmatory technique. Furthermore, good agreement was found between the γ-glutamyl-SeMC species concentrations obtained using both calibration methods.     

The reactions of alkylamino substituted phosphines with I2 and (Ph2Se2I2)2: structural features of alkylamino phosphonium cations

The reactions of the tris-dialkylamino phosphines (Et2N)3P and (nPr2N)3P, and the pyrrolidinyl substituted phosphines (C4H8N)3P and tBuP(NC4H8)2, with I2 and (Ph2Se2I2)2, have been reported. The reactions with diiodine lead to the formation of [R3PI]I adducts, which are essentially ionic, but show a tendency to display long, soft-soft, II interactions in the solid state. The crystal structures of [(Et2N)3PI]I, (1), [(nPr2N)3PI]I, (2), and [(C4H8N)3PI]I, (3), have all been determined, and display II interactions varying between 3.5170(6) and 3.6389(14) A. The analogous reactions with (Ph2Se2I2)2 lead to the formation of phenylseleno-phosphonium salts, [R3PSePh]I. The structures of [(C4H8N)3PSePh]I, (6) and [(C4H8N)2tBuPSePh] I, (7), have been determined and do not display any soft-soft interactions between the selenium and iodine atoms. All of the phosphonium salts represent examples of structures containing tris-dialkylamino phosphine fragments which show no special nitrogen atom, i.e. all three nitrogen atoms are planar. This type of arrangement is usually observed when a C3 symmetric conformation is observed, (which is the case for 1 and 2), but not for the (C4H8N)3P adducts 3 and 6, where the conformation is closer to Cs, although the nitrogen atoms are still essentially planar. The P-N bonds in all the compounds reported herein are short, ranging between 1.599(12) A and 1.643(12) A, and are consistent with the previously reported short P-N bonds in phosphonium salts featuring tris-dialkylamino substituted phosphines.     

Annular structures as intermediates in fibril formation of Alzheimer Abeta17-42

We report all-atom molecular dynamics simulations of annular beta-amyloid (17-42) structures, single- and double-layered, in solution. We assess the structural stability and association force of Abeta annular oligomers associated through different interfaces, with a mutated sequence (M35A), and with the oxidation state (M35O). Simulation results show that single-layered annular models display inherent structural instability: one is broken down into linear-like oligomers, and the other collapses. On the other hand, a double-layered annular structure where the two layers interact through their C-termini to form an NC-CN interface (where N and C are the N and C termini, respectively) exhibits high structural stability over the simulation time due to strong hydrophobic interactions and geometrical constraints induced by the closed circular shape. The observed dimensions and molecular weight of the oligomers from atomic force microscopy (AFM) experiments are found to correspond well to our stable double-layered model with the NC-CN interface. Comparison with K3 annular structures derived from the beta 2-microglobulin suggests that the driving force for amyloid formation is sequence specific, strongly dependent on side-chain packing arrangements, structural morphologies, sequence composition, and residue positions. Combined with our previous simulations of linear-like Abeta, K3 peptide, and sup35-derived GNNQQNY peptide, the annular structures provide useful insight into oligomeric structures and driving forces that are critical in amyloid fibril formation.     

Conformational preferences of beta- and gamma-aminated proline analogues

Quantum mechanical calculations have been used to investigate how the incorporation of an amino group to the Cbeta- or Cgamma-positions of the pyrrolidine ring affects the intrinsic conformational properties of the proline. Specifically, a conformational study of the N-acetyl-N'-methylamide derivatives of four isomers of aminoproline, which differ not only in the beta- or gamma-position of the substituent but also in its cis or trans relative disposition, has been performed. To further understand the role of the intramolecular hydrogen bonds between the backbone carbonyl groups and the amino side group, a conformational study was also performed on the corresponding four analogues of (dimethylamino)proline. In addition, the effects of solvation on aminoproline and (dimethylamino)proline dipeptides have been evaluated using a self-consistent reaction field model, and considering four different solvents (carbon tetrachloride, chloroform, methanol and water). Results indicate that the incorporation of the amino substituent into the pyrrolidine ring affects the conformational properties, with backbone...side chain intramolecular hydrogen bonds detected when it is incorporated in a cis relative disposition. In general, the incorporation of the amino side group tends to stabilize those structures where the peptide bond involving the pyrrolidine nitrogen is arranged in cis. The aminoproline isomer with the substituent attached to the Cgamma-position with a cis relative disposition is the most stable in the gas phase and in chloroform, methanol and water solutions. Replacement of the amino side group by the dimethylamino substituent produces significant changes in the potential energy surfaces of the four investigated (dimethylamino)proline-containing dipeptides. Thus, these changes affect not only the number of minima, which increases considerably, but also the backbone and pseudorotational preferences. In spite of these effects, comparison of the conformational preferences, i.e., the more favored conformers, calculated for different isomers of aminoproline and (dimethylamino)proline dipeptides showed a high degree of consistency for the two families of compounds.     

Structural analysis of a beta-helical protein motif stabilized by targeted replacements with conformationally constrained amino acids

Here we study conformational stabilization induced in a beta-helical nanostructure by position-specific mutations. The nanostructure is constructed through the self-assembly of the beta-helical building block excised from E. coli galactoside acetyltransferase (PDB code 1krr , chain A; residues 131-165). The mutations involve substitutions by cyclic, conformationally constrained amino acids. Specifically, a complete structural analysis of the Pro-Xaa-Val sequence [with Xaa being Gly, Ac 3c (1-aminocyclopropane-1-carboxylic acid) and Ac 5c (1-aminocyclopentane-1-carboxylic acid)], corresponding to the 148-150 loop region in the wild-type (Gly) and mutated (Ac 3c and Ac 5c) 1krr , has been performed using Molecular Dynamics simulations and X-ray crystallography. Simulations have been performed for the wild-type and mutants of three different systems, namely the building block, the nanoconstruct and the isolated Pro-Xaa-Val tripeptide. Furthermore, the crystalline structures of five peptides of Pro-Xaa-Val or Xaa-Val sequences have been solved by X-ray diffraction analysis and compared with theoretical predictions. Both the theoretical and crystallographic studies indicate that the Pro-Ac n c-Val sequences exhibit a high propensity to adopt turn-like conformations, and this propensity is little affected by the chemical environment. Overall, the results indicate that replacement of Gly149 by Ac 3c or Ac 5c significantly reduce the conformational flexibility of the target site enhancing the structural specificity of the building block and the nanoconstruct derived from the 1krr beta-helical motif.     

A Deeper Understanding of Metal Nucleation and Growth in Rechargeable Metal Batteries Through Theory and Experiment

Lithium and sodium metal batteries continue to occupy the forefront of battery research. Their exceptionally high energy density and nominal voltages are highly attractive for cutting-edge energy storage applications. Anode-free metal batteries are also coming into the research spotlight offering improved safety and even higher energy densities than conventional metal batteries. However, uneven metal nucleation and growth which leads to dendrites continues to limit the commercialisation of conventional and anode-free metal batteries alike. This review connects models and theories from well-established fields in metallurgy and electrodeposition to both conventional and anode-free metal batteries. These highly applicable models and theories explain the driving forces of uneven metal growth and can inform future experiment design. Finally, the models and theories that are most relevant to each anode-related cell component are identified. Keeping these specific models and theories in mind will assist with rational design for these components.