An analytical method for cyclosporine using liquid chromatography–mass spectrometry

A liquid chromatographic mass spectrometric (LC‐MS) assay has been developed for cyclosporine A (CyA) in rat plasma using amiodarone as internal standard (IS). Rat plasma (100 µL) containing drug and IS were extracted using liquid–liquid extraction with 4 mL of 95:5 ether:methanol. After evaporation of the organic layer the residue was reconstituted with 500 µL of water. Then the aqueous layer was transferred to LC‐MS sample vials. A 10 µL volume was injected. The analysis was performed on a C₈ column 3.5 µm (2.1 × 50 mm) heated to 60°C with a mobile phase consisting of acetonitrile:methanol:0.2% NH₄OH (60:20:20) at an isocratic flow‐rate of 0.2 mL/min. The ions used for quantitation of CyA and IS were m/z 1202.8 and 645.9, with retention times of 3.35 and 4.72 min, respectively. Linear relationships (r² > 0.99) were achieved between plasma or blood concentration and peak height ratios (drug:IS) over the concentration range 50–5000 ng/mL. The CV% and mean error were <19%. Based on validation data, the lower limit of quantification for the assay was 50 ng/mL. The reported assay method displayed high measures of linearity, sensitivity, reliability and precision, allowing its applicability in pharmacokinetic studies in rat. Copyright © 2009 John Wiley & Sons, Ltd.     

Stability and bonding of carbon(0)-iron−N2 complexes relevant to nitrogenase co-factor: EDA-NOCV analyses

The factors/structural features which are responsible for the binding, activation and reduction of N₂ to NH₃ by FeMoco of nitrogenase have not been completely understood well. Several relevant model complexes by Holland et al. and Peters et al. have been synthesized, characterized and studied by theoretical calculations. For a matter of fact, those complexes are much different than real active N₂-binding Fe-sites of FeMoco, which possesses a central C(4-) ion having an eight valence electrons as an μ₆-bridge. Here, a series of [(S₃C(0))Fe(II/I/0)-N₂]^n- complexes in different charged/spin states containing a coordinated σ- and π-donor C(0)-atom which possesses eight outer shell electrons [carbone, (Ph₃P)₂C(0); Ph₃P→C(0)←PPh₃] and three S-donor sites (i.e. ^-S-Ar), have been studied by DFT, QTAIM, and EDA-NOCV calculations. The effect of the weak field ligand on Fe-centres and the subsequent N₂-binding has been studied by EDA-NOCV analysis. The role of the oxidation state of Fe and N₂-binding in different charged and spin states of the complex have been investigated by EDA-NOCV analyses. The intrinsic interaction energies of the Fe−N₂ bond are in the range from −42/−35 to −67 kcal/mol in their corresponding ground states. The S₃C(0) donor set is argued here to be closer to the actual coordination environment of one of the six Fe-centres of nitrogenase. In comparison, the captivating model complexes reported by Holland et al. and Peter et al. possess a stronger π-acceptor C-ring (S₂C_ring donor, π-C donor) and stronger donor set like CP₃ (σ-C donor) ligands, respectively.     

Synthesis of acridinedione derivatives as laser dyes

Synthesis of 9-alkyl, 10-alkyl, 9,10-dialkyl, and 10-aryl-3,4,6,7,9,10-hexahydro-1,8(2H,5H)acridinedione (2a–r) are described as a new class of laser dyes. Reactions of diamines with methylene bis(cyclohexane-1,3-dione) yielded the respective bisacridinediones (3a–e). These dyes lase around 478–494 nm and are compared with the standard dye coumarin-102. © 1996 John Wiley & Sons, Inc.     

Oscillating multidromion excitations in higher-dimensional nonlinear lattice with intersite and external on-site potentials using symbolic computation

We show by an extensive method of quasi-discrete multiple-scale approximation that nonlinear multi-dimensional lattice waves subjected to intersite and external on-site potentials are found to be governed by (N +1)-dimensional nonlinear Schro¨dinger (NLS) equation. In particular, the resonant mode interaction of (2+1)-dimensional NLS equation has been identified and the theory allows the inclusion of transverse effect. We apply the exponential function method to the (2+1)-dimensional NLS equation and obtain the class of soliton solutions with a purely algebraic computational method. Notably, we discuss in detail the effects of the external on-site potentials on the explicit form of the soliton solution generated recursively. Under the action of the external on-site potentials, the model presents a rich variety of oscillating multidromion patterns propagating in the system.     

Triclabendazole: An Intriguing Case of Co‐existence of Conformational and Tautomeric Polymorphism

The crystal polymorphism of the anthelmintic drug, triclabendazole ( TCB ), is described. Two anhydrates (Forms I and II), three solvates, and an amorphous form have been previously mentioned. This study reports the crystal structures of Forms I ( 1 ) and II ( 2 ). These structures illustrate the uncommon phenomenon of tautomeric polymorphism. TCB exists as two tautomers A and B. Form I (Z′=2) is composed of two molecules of tautomer A while Form II (Z′=1) contains a 1:1 mixture of A and B. The polymorphs are also characterized by using other solid‐state techniques (differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), PXRD, FT‐IR, and NMR spectroscopy). Form I is the higher melting form (m.p.: 177 °C, ΔH_f=≈105±4 J g^?1) and is the more stable form at room temperature. Form II is the lower melting polymorph (m.p.: 166 °C, ΔH_f=≈86±3 J g^?1) and shows high kinetic stability on storage in comparison to the amorphous form but it transforms readily into Form I in a solution‐mediated process. Crystal structure analysis of co‐crystals 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 further confirms the existence of tautomeric polymorphism in TCB . In 3 and 11 , tautomer A is present whereas in 4 , 5 , 6 , 7 , 8 , 9 , 10 the TCB molecule exists wholly as tautomer B. The DFT calculations suggest that the optimized tautomers A and B have nearly the same energies. Single point energy calculations reveal that tautomer A (in Form I) exists in two low‐energy conformations, whereas in Form II both tautomers A and B exist in an unfavorable high‐energy conformation, stabilized by a five‐point dimer synthon. The structural and thermodynamic features of 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 are discussed in detail. Triclabendazole is an intriguing case in which tautomeric and conformational variations co‐exist in the polymorphs.     

A highly efficient, mild, and selective cleavage of beta-methoxyethoxymethyl (MEM) ethers by cerium(III) chloride in acetonitrile

[structure: see text]. A highly selective cleavage of MEM ethers has been achieved in high yields using CeCl3.7H2O in refluxing acetonitrile under mild and neutral reaction conditions. The method is very rapid and compatible with other hydroxyl protecting groups such as Bn, TBDPS, Ac, Me, Tr, PMB, benzylidene, THP, MOM, BOM, and NHAc present in the substrate.     

Solid-State Isolation of Cyclic Alkyl(Amino) Carbene (cAAC)-Supported Structurally Diverse Alkali Metal-Phosphinidenides

Cyclic alkyl(amino) carbene (cAAC)-supported, structurally diverse alkali metal-phosphinidenides 2 – 5 of general formula ((cAAC)P-M)_n(THF)_x [ 2 : M=K, n=2, x=4; 3 : M=K, n=6, x=2; 4 : M=K, n=4, x=4; 5 : M=Na, n=3, x=1] have been synthesized by the reduction of cAAC-stabilized chloro-phosphinidene cAAC=P-Cl ( 1 ) utilizing metallic K or KC₈ and Na-naphthalenide as reducing agents. Complexes 2 – 5 have been structurally characterized in solid state by NMR studies and single crystal X-ray diffraction. The proposed mechanism for the electron transfer process has been well-supported by cyclic voltammetry (CV) studies and Density Functional Theory (DFT) calculations. The solid state oligomerization process has been observed to be largely dependent on the ionic radii of alkali metal ions, steric bulk of cAAC ligands and solvation/de-solvation/recombination of the dimeric unit [(cAAC)P-M(THF)_x]₂.     

Determination of the line tension of giant vesicles from pore-closing dynamics

Giant vesicles generated from synthetic and natural lipids such as phosphatidylcholines are useful models for understanding mechanical properties of cell membranes. Line tension is the one-dimensional force enabling the closing of transient pores on cell membranes. Transient pores were repeatedly and reproducibly formed on the membrane edge of giant vesicles generated from synthetic and natural phosphatidylcholines employing a nitrogen-pumped coumarin dye laser (440 nm). Line tension was determined at room temperature from closing of these pores that occurred over several seconds when the radius of the vesicle could be considered to be constant. The value of line tension depends on the nature of the lipid for single lipid systems, which, at room temperature, yielded a vesicle bilayer region in the gel, fluid, or mixed gel and fluid phases. The line tension for vesicles generated from phosphatidylcholines with saturated acyl chains of lengths of 12-18 carbon atoms ranges from 1 to 12 pN, exhibiting an increase with chain length. Vesicles generated from the natural Egg-PC, which is a mixture of lipids, are devoid of phase transition and exhibited the largest value of line tension (32 pN). This value is much larger than that estimated from the line tensions of vesicles obtained from lipids with homologous acyl chains. This study, to our knowledge, is the first to employ laser ablation to generate transient pores and determine line tension from the rate of pore closure and demonstrate a relationship between line tension and acyl chain length.     

Chemical Bonding in Homoleptic Carbonyl Cations [M{Fe(CO)5}2]+ (M=Cu,Ag, Au)

Syntheses of the copper and gold complexes [Cu{Fe(CO)₅}₂][SbF₆] and [Au{Fe(CO)₅}₂][HOB{3,5-(CF₃)₂C₆H₃}₃] containing the homoleptic carbonyl cations [M{Fe(CO)₅}₂]⁺ (M=Cu, Au) are reported. Structural data of the rare, trimetallic Cu₂Fe, Ag₂Fe and Au₂Fe complexes [Cu{Fe(CO)₅}₂][SbF₆], [Ag{Fe(CO)₅}₂][SbF₆] and [Au{Fe(CO)₅}₂][HOB{3,5-(CF₃)₂C₆H₃}₃] are also given. The silver and gold cations [M{Fe(CO)₅}₂]⁺ (M=Ag, Au) possess a nearly linear Fe-M-Fe’ moiety but the Fe-Cu-Fe’ in [Cu{Fe(CO)₅}₂][SbF₆] exhibits a significant bending angle of 147° due to the strong interaction with the [SbF₆]⁻ anion. The Fe(CO)₅ ligands adopt a distorted square-pyramidal geometry in the cations [M{Fe(CO)₅}₂]⁺, with the basal CO groups inclined towards M. The geometry optimization with DFT methods of the cations [M{Fe(CO)₅}₂]⁺ (M=Cu, Ag, Au) gives equilibrium structures with linear Fe-M-Fe’ fragments and D₂ symmetry for the copper and silver cations and D_4d symmetry for the gold cation. There is nearly free rotation of the Fe(CO)₅ ligands around the Fe-M-Fe’ axis. The calculated bond dissociation energies for the loss of both Fe(CO)₅ ligands from the cations [M{Fe(CO)₅}₂]⁺ show the order M=Au (D_e=137.2 kcal mol⁻¹)>Cu (D_e=109.0 kcal mol⁻¹)>Ag (D_e=92.4 kcal mol⁻¹). The QTAIM analysis shows bond paths and bond critical points for the M−Fe linkage but not between M and the CO ligands. The EDA-NOCV calculations suggest that the [Fe(CO)₅]→M⁺←[Fe(CO)₅] donation is significantly stronger than the [Fe(CO)₅]←M⁺→[Fe(CO)₅] backdonation. Inspection of the pairwise orbital interactions identifies four contributions for the charge donation of the Fe(CO)₅ ligands into the vacant (n)s and (n)p AOs of M⁺ and five components for the backdonation from the occupied (n-1)d AOs of M⁺ into vacant ligand orbitals.     

Stabilization of Linear C3 by Two Donor Ligands: A Theoretical Study of L-C3-L (L=PPh3, NHCMe,cAACMe)**

Quantum chemical studies using density functional theory and ab initio methods have been carried out for the molecules L-C₃-L with L=PPh₃ ( 1 ), NHC^Me ( 2 , NHC=N-heterocyclic carbene), and cAAC^Me ( 3 , cAAC=cyclic (alkyl)(amino) carbene). The calculations predict that 1 and 2 have equilibrium geometries where the ligands are bonded with rather acute bonding angles at the linear C₃ moiety. The phosphine adduct 1 has a synclinal (gauche) conformation whereas 2 exhibits a trans conformation of the ligands. In contrast, the compound 3 possesses a nearly linear arrangement of the carbene ligands at the C₃ fragment. The bond dissociation energies of the ligands have the order 1 < 2 < 3 . The bonding analysis using charge and energy decomposition methods suggests that 3 is best described as a cumulene with electron-sharing double bonds between neutral fragments (cAAC^Me)₂ and C₃ in the respective electronic quintet state yielding (cAAC^Me)=C₃=(cAAC^Me). In contrast, 1 and 2 possess electron-sharing and dative bonds between positively charged ligands [(PPh₃)₂]⁺ or [(NHC^Me)₂]⁺ and negatively charged [C₃]⁻ fragments in the respective doublet state.