Development and validation of a liquid chromatography-ultraviolet absorbance detection assay using derivatisation for the novel marine anticancer agent ES-285 x HCl [(2S,3R)-2-amino-3-octadecanol hydrochloride] and its pharmaceutical dosage form

ES-285 x HCl [(2S,3R)-2-amino-3-octadecanol hydrochloride] is a novel investigational anticancer agent, which has shown in vitro and in vivo cytotoxic activity against various tumor cell lines with selectivity for certain solid tumors. The pharmaceutical development of ES-285 x HCl warranted the availability of an assay for the quantification and purity determination of ES-285 x HCl active pharmaceutical ingredient (API) and its pharmaceutical dosage form. A liquid chromatographic method (LC) comprising of derivatisation of ES-285 x HCl with phenylisothiocyanate and UV-detection was developed. The method was found to be linear, precise and accurate. The assay also proved selectivity as determined by analysing ES-285 x HCl in combination with 15 analogues and in combination with hydroxypropyl-beta-cyclodextrin, the excipient used in the lyophilised pharmaceutical dosage form. Stress testing showed that the degradation products were separated from the parent compound, confirming its stability indicating capacity. The method was found robust as determined with design of experiments (DoE), which made it possible to predict system suitability responses in worst case experimental conditions and to define criteria for system suitability testing.     

Assembly of colloidal particles into microwires using an alternating electric field

We have investigated the dielectrophoretic assembly of colloidal gold, carbon black, and carbon nanotubes into electrical wires. The resulting microwires have diameters less than 1 microm, with lengths ranging from 5 microm to 3 mm. Current-voltage curves for these wires indicate an ohmic response, where the resistance is determined by the type of colloid and by the frequency of the alternating field used to grow the wires. The predicted frequency dependence of dielectrophoresis is confirmed by experiment. Measurements of the threshold voltage for initial wire growth are also presented. These experiments demonstrate that a variety of nanoparticles can be assembled into microwires for sensor applications.     

Enzyme electrokinetics: electrochemical studies of the anaerobic interconversions between active and inactive states of Allochromatium vinosum [NiFe]-hydrogenase

The cycling between active and inactive states of the catalytic center of [NiFe]-hydrogenase from Allochromatium vinosum has been investigated by dynamic electrochemical techniques. Adsorbed on a rotating disk pyrolytic graphite "edge" electrode, the enzyme is highly electroactive: this allows precise manipulations of the complex redox chemistry and facilitates quantitative measurements of the interconversions between active catalytic states and the inactive oxidized form Ni(r) (also called Ni-B or "ready") as functions of pH, H(2) partial pressure, temperature, and electrode potential. Cyclic voltammograms for catalytic H(2) oxidation (current is directly related to turnover rate) are highly asymmetric (except at pH > 8 and high temperature) due to inactivation being much slower than activation. Controlled potential-step experiments show that the rate of oxidative inactivation increases at high pH but is independent of potential, whereas the rate of reductive activation increases as the potential becomes more negative. Indeed, at 45 degrees C, activation takes just a few seconds at -288 mV. The cyclic asymmetry arises because interconversion is a two-stage reaction, as expected if the reduced inactive Ni(r)-S state is an intermediate. The rate of inactivation depends on a chemical process (rearrangement and uptake of a ligand) that is independent of potential, but sensitive to pH, while activation is driven by an electron-transfer process, Ni(III) to Ni(II), that responds directly to the driving force. The potentials at which fast activation occurs under different conditions have been analyzed to yield the potential-pH dependence and the corresponding entropies and enthalpies. The reduced (active) enzyme shows a pK of 7.6; thus, when a one-electron process is assumed, reductive activation at pH < 7 involves a net uptake of one proton (or release of one hydroxide), whereas, at pH > 8, there is no net exchange of protons with solvent. Activation is favored by a large positive entropy, consistent with the release of a ligand and/or relaxation of the structure around the active site.     

Influence des charges nucléaires effectives σ et π sur les calculs LCAO-MO-SCF-π

Application of the LCAO-MO-SCF- method to conjugated hydrocarbons leads with the effective nuclear Slater's charges, Z_eff = Z_eff = 3.25 to electronic transitions higher than experimental ones by about 50%.We show that in the case of all trans linear polyenes and fulvene, one may obtain satisfying results by the same method, without any reference to experience, by taking Z_eff = 3.0 Z_eff = 3.55. There the effective nuclear charges are near of these of the valence state of carbon V ₄1s²t₁t₂t₃2pt_z:Z_eff = 2.971 Z_eff = 3.382 [10].     

Measurement of the kinetic isotope effect for the oxidation of NADH at a poly(aniline)-modified electrode

Kinetic isotope measurements using [4,4-2H2]NADH and [4-1H, 4-2H]NADH have been used to investigate the mechanism of the electrochemical oxidation of NADH at poly(aniline)-poly(vinyl sulfonate)-modified electrodes. The experiments show a primary kinetic isotope effect for the reaction of 4.2. This is consistent with literature values for the corresponding isotope effect for the oxidation of NADH by two-electron oxidants in homogeneous solution. The result demonstrates that transfer of H from NADH to the modified electrode occurs in the rate-limiting step within the reaction complex.     

Factors affecting metal-metal bonding in the face-shared d(3)d(3) bioctahedral dimer systems,MM'Cl(9)(5-) (M,M' = V,Nb, Ta)

Density functional theory (DFT) calculations have been used to investigate the d(3)d(3) bioctahedral complexes, MM'Cl(9)(5-), of the vanadium triad. Broken-symmetry calculations upon these species indicate that the V-containing complexes have optimized metal-metal separations of 3.4-3.5 A, corresponding to essentially localized magnetic electrons. The metal-metal separations in these weakly coupled dimers are elongated as a consequence of Coulombic repulsion, which profoundly influences (and destabilizes) the gas-phase structures for such dimers; nevertheless, the intermetallic interactions in the V-containing dimers involve significantly greater metal-metal bonding character than in the analogous Cr-containing dimers. These observations all show good agreement with existing experimental (solid state) results for the chloride-bridged, face-shared dimers V(2)Cl(9)(5-) and V(2)Cl(3)(thf)(6)(+). In contrast to the V-containing dimers, complexes featuring only Nb and Ta have much shorter intermetallic distances (approximately 2.4 A) consistent with d-electron delocalization and formal metal-metal triple bond formation; again, good agreement is found with available experimental data. Calculations on the complexes V(2)(mu-Cl)(3)(dme)(6)(+), Nb(2)(mu-dms)(3)Cl(6)(2-), and Ta(2)(mu-dms)(3)Cl(6)(2-), which are closely related to compounds for which crystallographic structural data exist, have been pursued and provide an insight into the intermetallic interactions in the experimentally characterized complexes. Analysis of the contributions from d-orbital overlap (E(ovlp)) stabilization, as well as spin polarization (exchange) stabilization of localized d electrons (E(spe)), has also been attempted for the MM'Cl(9)(5-) dimers. While E(ovlp) clearly dominates over E(spe) as a stabilizing factor in those dimers containing only Nb and Ta metal atoms, detailed assessment of the competition between E(ovlp) and E(spe) for V-containing dimers is obstructed by the instability of triply bonded V-containing dimers against Coulombic explosion. On the basis of the periodic trends in E(ovlp) versus E(spe), the V-triad dimers have a greater propensity for metal-metal bonding than do their Cr-triad or Mn-triad counterparts.     

Herstellung von 6,14-Ethenomorphinan-Derivaten

Zusammenfassung Dihydronorthevinon (2b) wurde aus Dihydrothevinon (2a) mit Azodicarbonsäurediethylester (DEAD) hergestellt und zu einigen neuen N-substituierten Dihydronorthevinon-Derivaten (2c–2g) umgesetzt. Es wurdenGrignard-Reaktionen dieser Verbindungen mit Methylmagnesiumiodid bzw.tert-Butylmagnesiumchlorid durchgeführt. O-Demethylierungen von3a–3j ergaben die entsprechenden N-substituierten Buprenorphin- bzw. Diprenorphin-Analoga4a–4j.

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Preparation of 6,14-ethenomorphinan derivatives

Summary Dihydronorthevinone (2b) was prepared from dihydrothevinone (2a) with diethyl azodicarboxylate (DEAD) and transformed into a number of new N-substituted dihydronorthevinone derivatives (2c–2g).Grignard reactions of the new compounds with methylmagnesium iodide andtert-butyl-magnesium chloride were studied. O-Demethylation of3a–3j resulted in the corresponding N-substituted buprenorphine and diprenorphine analogs4a–4j.

     

Chiral Compounds Synthesized by Biocatalytic Reductions [New Synthetic Methods (51)]

It has been known for many decades that chiral compounds can be obtained by stereospecific biocatalytic reduction. Further significant methodological developments in this field have, however, only been made during the past ten years; they include the application of previously unused microorganisms and electron donors, the discovery of additional substrates for the known reductases, the development of methods for regenerating reduced pyridine nucleotides, and the discovery of new reductases which were sought for specific preparative purposes. Many chiral compounds can now be synthesized by microbial hydrogenation using H₂ and hydrogenase-containing microorganisms as well as by electromicrobial or electroenzymatic reduction. In the two latter methods, anaerobic or aerobic organisms are supplied with electrons from electrochemically reduced, artificial mediators, e.g., methyl viologen. Reductases that do not require pyridine nucleotides and can accept electrons directly from reduced viologens are especially useful. Two examples of this type of enzyme are described which are of preparative interest. Many cells contain methyl viologen-dependent NAD(P) reductases, a large number of which have still not been characterized. A productivity number is proposed which allows different methods of bioconversion with microorganisms to be compared. The productivity numbers of compounds synthesized by the methods described in this review are often 10- to 100-fold higher than those of substances obtained by conventional techniques.     

A Simple proof of the generalized electrostatic Israel theorem

A simple proof of a generalization of the theorem of Israel concerning the uniqueness of the Reissner-Nordström black holes is presented. The present method is also applied to show, in the bosonic sector ofN=4-supergravity, the uniqueness of a static black hole solution found by Gibbons.Work supported by Fonds zur Förderung der wissenschaftlichen Forschung in Österreich, Project No. 4961.     

Gravitational field strength and generalized Komar integral

We define a gravitational field strength in theories of the Einstein-Cartan type admitting a Killing vector. This field strength is a second rank, antisymmetric, divergence-free tensor, whose (Komar) integral over a closed 2-surface gives a physically meaningful quantity. We find conditions on the Lagrange density of the theory which ensure the existence of such a tensor, and show that they are satisfied forN=2-supergravity and for a special case of the bosonic sector ofN=4-supergravity. We discuss a possible application of the generalized Komar integral in the theory of stationary black holes. We also consider the field strength problem in Kaluza-Klein theory, where the application to black holes is particularly interesting.