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1.
Dr. Christoph Hirschhäuser Dr. Juraj Velcicky Dr. Daniel Schlawe Dr. Erik Hessler Dr. André Majdalani Dr. Jörg‐Martin Neudörfl Dr. Dr. Aram Prokop Dr. Thomas Wieder Prof. Dr. Hans‐Günther Schmalz 《Chemistry (Weinheim an der Bergstrasse, Germany)》2013,19(39):13017-13029
The synthesis and stereochemical assignment of two classes of iron‐containing nucleoside analogues, both of which contain a butadiene? Fe(CO)3 substructure, is described. The first type of compounds are Fe(CO)3‐complexed 3′‐alkenyl‐2′,3′‐dideoxy‐2′,3′‐dehydro nucleosides (2,5‐dihydrofuran derivatives), from which the second class of compounds is derived by formal replacement of the ring oxygen atom by a CH2 group (carbocyclic nucleoside analogues). These compounds were prepared in a stereoselective manner through the metal‐assisted introduction of the nucleobase. Whilst the furanoid intermediates were prepared from carbohydrates (such as methyl‐glucopyranoside), the carbocyclic compounds were obtained by using an intramolecular Pauson–Khand reaction. Stereochemical assignments based on NMR and CD spectroscopy were confirmed by X‐ray structural analysis. Biological investigations revealed that several of the complexes exhibited pronounced apoptosis‐inducing properties (through an unusual caspase 3‐independent but ROS‐dependent pathway). Furthermore, some structure–activity relationships were identified, also as a precondition for the design and synthesis of fluorescent and biotin‐labeled conjugates. 相似文献
2.
Velcicky J Lanver A Lex J Prokop A Wieder T Schmalz HG 《Chemistry (Weinheim an der Bergstrasse, Germany)》2004,10(20):5087-5110
A diversity-oriented, enantioselective synthesis of new (monoprotected) carbocyclic nucleoside analogues (CNAs) with the nucleobase attached to a 3-hydroxymethyl-4-trialkylsilyloxymethylcyclopent-2-en-1-yl scaffold was developed. As a key intermediate, racemic (5SR,8RS)-8-allyloxy-2-trimethylsilyl-7-oxa-bicyclo[3.3.0]-oct-1-en-3-one was prepared from 1,1-diallyloxy-3-trimethylsilyl-2-propyne in a cobalt-mediated Pauson-Khand reaction. The enantiomerically pure material was obtained through efficient kinetic resolution (selectivity factor s >/= 40 at -78 degrees C) by means of an oxazaborolidine-catalyzed borane reduction (CBS reduction) with catecholborane. The absolute configuration of the resolved products was determined by CD spectroscopy, Mosher ester analysis, and chemical correlation. Subsequent steps involve diastereoselective ketone reduction and fully regio- and diastereoselective introduction of the nucleobase through Pd(0)-catalyzed allylic substitution. The generality of the method was demonstrated by preparation of CNAs in both enantiomeric series with all five natural nucleobases, as well as 5-bromouracil, 5-fluorouracil, and 6-chloropurine. Screening of the various compounds in a cytotoxicity assay with BJAB and ALL tumor cell lines revealed that some of the compounds possess pronounced antitumoral properties (LD50 values down to 9 microM, as determined by lactate dehydrogenase release after 48 h). By measuring DNA fragmentation, it could be shown that the activity results from induction of apoptosis. 相似文献
3.
T. Axenrod C. M. Watnick M. J. Wieder S. Duangthai G. A. Webb H. J. C. Yeh S. Bulusu M. M. King 《Magnetic resonance in chemistry : MRC》1982,20(1):11-15
The 1J(15N13C) values for a series of ring-substituted N,N-dimethylaniline-15N derivatives and a series of nitrobenzene-15N derivatives were measured from the 13C spectra. In the nitrobenzenes, small changes in 1J(15N13C) are attributed to the inductive effect of the substituents, since steric inhibition of conjugation has little effect on the magnitude of the coupling. In contrast, steric inhibition of nitrogen lone-pair delocalization in N,N-dimethylaniline derivatives markedly reduces the value of 1J(15N13C). Theoretical calculations of 1J(15N13C) values for the two series of compounds were made using standard INDO parameters and a ‘sum-over-states’ perturbation approach. Fair agreement between the calculated and experimental values is found. 相似文献
4.
A technique for measuring absorption from excited states with nanosecond lifetimes utilizing pulsed tunable dye laser probes is described. The method features a simple experimental set-up, and high signal-to-noise ratio. The excited singlet state absorption spectrum of one transition in acridine red is presented. 相似文献
5.
Vicinal 15N–H coupling constants are used to characterize the isomeric pyrazoles obtained from the condensation of phenylhydrazine, 15N-enriched at the amino nitrogen atom, with various 1,3-diketones. 相似文献
6.
In the present work, poly(glycidyl methacrylate-co-divinylbenzene) monoliths were synthesized and further derivatized to obtain strong anion exchange supports. Capillary monoliths (65 x 0.2 mm id) were prepared in situ by copolymerization of glycidyl methacrylate and divinylbenzene, employing 1-decanol and tetrahydrofuran as porogens. The free epoxy groups were derivatized in a two step synthesis to obtain quaternary ammonium functionalities. On testing the pressure stability of the synthesized monolith, a highly linear dependence between flow rate and pressure drop was obtained, indicating the high stability of the material even at high flow rates. The morphology of the copolymer was investigated by scanning electron microscopy. Mercury intrusion porosimetry showed a narrow pore size distribution, having a maximum at 439 nm. On recording a van Deemter plot the number of theoretical plates per meter was found to be 59324. The produced strong anion exchange monoliths turned out to be highly suitable for the separation of nucleotides and oligonucleotides. 相似文献
7.
A. Hohl T. Wieder P. A. van Aken T. E. Weirich G. Denninger M. Vidal S. Oswald C. Deneke J. Mayer H. Fuess 《Journal of Non》2003,320(1-3):255-280
The present state of research on the structure of amorphous silicon monoxide (SiO) is reviewed. The black, coal-like modification of bulk SiO is studied by a combination of diffraction, microscopy, spectroscopy, and magnetometry methods. Partial radial distribution functions of SiO are obtained by X-ray, neutron and electron diffraction. Disproportionation of SiO into Si and SiO2 is verified. High resolution TEM gives an upper limit of less than 2 nm for the typical Si cluster size. The Si K-edge electron energy-loss near-edge structure (ELNES) data of SiO are interpreted in terms of the oxidation states Si4+ and Si0. X-ray photoelectron spectroscopy gives first details about possible stoichiometric inhomogeneities related to internal interfaces. The wipe-out effect in the 29Si MAS NMR signal of SiO is confirmed experimentally. The new estimation of the wipe-out radius is about 1.1 nm. First-time W-band, Q-band, and X-band ESR and SQUID measurements indicate an interfacial defect structure. Frequency distributions of atomic nearest-neighbours are derived. The interface clusters mixture model (ICM model) suggested here describes the SiO structure as a disproportionation in the initial state. The model implies clusters of silicon dioxide and clusters of silicon surrounded by a sub-oxide matrix that is comparable to the well-known thin Si/SiO2 interface and significant in the volume because of small cluster sizes. 相似文献
8.
Novel monolithic supports (MS/BVPE) were prepared by thermally initiated free radical copolymerisation of p-methylstyrene (MS) and 1,2-bis(p-vinylphenyl)ethane (BVPE). The polymer was synthesised in fused silica capillaries (80 mm x 0.2 mm and 80 mm x 0.53 mm) and in borosilicate glass columns (90 mm x 1.0 mm and 90 mm x 3.0 mm) to yield different HPLC column designs. A comparison of those column dimensions regarding morphology as well as separation efficiency and applicability in bioanalysis is presented. The efficiency towards proteins as well as oligonucleotides was found to be considerably improved with decreasing column I.D. While a 5-protein mixture was baseline separated on all investigated column designs, the separation of small biomolecules like oligonucleotides or peptides on microbore and conventional size glass columns was strongly restricted in terms of resolution due to extensive peak broadening or the occurrence of peak asymmetry. Monolithic MS/BVPE capillary columns up to 0.53 mm I.D., however, proved to be applicable to the fractionation of the whole spectrum of biopolymers, including proteins, peptides, oligonucleotides as well as double-stranded DNA fragments. Due to the fact that reliable chromatography makes great demand on the robustness of the stationary phase, monolithic MS/BVPE capillaries were subjected to a comprehensive reproducibility study including run-to-run as well as batch-to-batch reproducibility. 相似文献
9.
The computation of tautomer ratios of druglike molecules is enormously important in computer-aided drug discovery, as over a quarter of all approved drugs can populate multiple tautomeric species in solution. Unfortunately, accurate calculations of aqueous tautomer ratios—the degree to which these species must be penalized in order to correctly account for tautomers in modeling binding for computer-aided drug discovery—is surprisingly difficult. While quantum chemical approaches to computing aqueous tautomer ratios using continuum solvent models and rigid-rotor harmonic-oscillator thermochemistry are currently state of the art, these methods are still surprisingly inaccurate despite their enormous computational expense. Here, we show that a major source of this inaccuracy lies in the breakdown of the standard approach to accounting for quantum chemical thermochemistry using rigid rotor harmonic oscillator (RRHO) approximations, which are frustrated by the complex conformational landscape introduced by the migration of double bonds, creation of stereocenters, and introduction of multiple conformations separated by low energetic barriers induced by migration of a single proton. Using quantum machine learning (QML) methods that allow us to compute potential energies with quantum chemical accuracy at a fraction of the cost, we show how rigorous relative alchemical free energy calculations can be used to compute tautomer ratios in vacuum free from the limitations introduced by RRHO approximations. Furthermore, since the parameters of QML methods are tunable, we show how we can train these models to correct limitations in the underlying learned quantum chemical potential energy surface using free energies, enabling these methods to learn to generalize tautomer free energies across a broader range of predictions.We show how alchemical free energies can be calculated with QML potentials to identify deficiencies in RRHO approximations for computing tautomeric free energies, and how these potentials can be learned from experiment to improve prediction accuracy. 相似文献
10.
M. E. Wieder B. P. Gray P. R. Brown S. Hudson C. M. Pearce S. W. Paine L. Hillyer 《Chromatographia》2012,75(11-12):635-643
Acepromazine maleate (Sedalin?) was administered orally to six thoroughbred horses at a dose of 0.15?mg?kg?1. Urine and blood samples were collected up to 412?h post-administration. Plasma and urine were hydrolysed; plasma samples were then processed using liquid–liquid extraction and urine samples using solid-phase extraction. A sensitive tandem mass spectrometric method was developed in this study, achieving a lower limit of quantification for acepromazine of 10?pg?mL?1 in plasma and 100?pg?mL?1 in urine. Acepromazine, hydroxyethylpromazine, hydroxyacepromazine, hydroxyethylpromazine sulphoxide, hydroxyethylhydroxypromazine, dihydroxyacepromazine and dihydroxyhydroxyethylpromazine were detected in the post-administration samples. The parent drug and its metabolites were identified using a combination of UPLC–MS/MS and accurate mass measurement. Separation of the structural isomers hydroxyethylpromazine sulphoxide and hydroxyethylhydroxypromazine was another significant outcome of this work and demonstrated the advantages to be gained from investing in chromatographic method development. 相似文献