The Experts below are selected from a list of 312 Experts worldwide ranked by ideXlab platform
Jan Kihlberg - One of the best experts on this subject based on the ideXlab platform.
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Use of 19F NMR Spectroscopy to screen chemical libraries for ligands that bind to proteins.
Organic & biomolecular chemistry, 2004Co-Authors: Tobias Tengel, Tomas Fex, Hans Emtenäs, Fredrik Almqvist, Ingmar Sethson, Jan KihlbergAbstract:Identification of compounds from chemical libraries that bind to macromolecules by use of NMR Spectroscopy has gained increasing importance during recent years. A simple methodology based on 19F NMR Spectroscopy for the screening of ligands that bind to proteins, which also provides qualitative information about relative binding strengths and the presence of multiple binding sites, is presented here. A library of fluorinated compounds was assembled and investigated for binding to the two bacterial chaperones PapD and FimC, and also to human serum albumin (HSA). It was found that library members which are bound to a target protein could be identified directly from line broadening and/or induced chemical shifts in a single, one-dimensional 19F NMR spectrum. The results obtained for binding to PapD using 19F NMR Spectroscopy agreed well with independent studies based on surface plasmon resonance, providing support for the versatility and accuracy of the technique. When the library was titrated to a solution of PapD chemical shift and linewidth changes were observed with increasing ligand concentration, which indicated the presence of several binding sites on PapD and enabled the assessment of relative binding strengths for the different ligands. Screening by 19F NMR Spectroscopy should thus be a valuable addition to existing NMR techniques for evaluation of chemical libraries in bioorganic and medicinal chemistry.
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Solid-Phase Synthesis of α-Gal Epitopes: On-Resin Analysis of Solid-Phase Oligosaccharide Synthesis with 19F NMR Spectroscopy
The Journal of organic chemistry, 2003Co-Authors: Mickael Mogemark, Mikael Elofsson, Jan KihlbergAbstract:A route for solid-phase synthesis of the α-Gal epitopes Gal(α1−3)Gal(β1−4)Glc and Gal(α1−3)Gal(β1−4)GlcNAc is described. These trisaccharide antigens are responsible for hyperacute rejection in xenotransplantation of porcine organs. Optimization of the solid-phase synthesis relied on use of fluorinated protective groups for the carbohydrate building blocks and use of a fluorinated linker. This allowed convenient on-resin analysis of the reactions with gel-phase 19F NMR Spectroscopy. Conditions were established which allowed reductive ring-opening of 4,6-O-benzylidene acetals to be performed on the solid phase with high regioselectivity to furnish the corresponding 6-O-benzyl ethers. It was found that glycosylations could be conveniently carried out by using thioglycosides as donors with N-iodosuccinimide and trifluoromethanesulfonic acid as the promoter system. With use of these conditions a challenging α-glycosidic linkage was successfully installed with complete stereoselectivity in the final glycosylat...
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Fluorinated protective groups for on-resin quantification of solid-phase oligosaccharide synthesis with 19F NMR Spectroscopy.
Chembiochem : a European journal of chemical biology, 2002Co-Authors: Mickael Mogemark, Mikael Elofsson, Jan KihlbergAbstract:Fluorinated Protective Groups for On-Resin Quantification of Solid- Phase Oligosaccharide Synthesis with 19F NMR Spectroscopy
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Monitoring Solid-Phase Glycoside Synthesis with 19F NMR Spectroscopy
Organic letters, 2001Co-Authors: Mickael Mogemark, Mikael Elofsson, Jan KihlbergAbstract:A simple and efficient method for monitoring and optimizing carbohydrate synthesis on polymeric support by using 19F NMR Spectroscopy is described. The method relies on the use of fluorinated variants of protective groups that are in common use in oligosaccharide synthesis.
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Preparation of fluorinated linkers: use of 19F NMR Spectroscopy to establish conditions for solid-phase synthesis of pilicide libraries.
Journal of combinatorial chemistry, 2000Co-Authors: Anette Svensson, Tomas Fex, Jan KihlbergAbstract:Three fluorinated linkers which are analogues of linkers commonly used in solid-phase peptide synthesis have been prepared. One of the linkers was used in combination with gel-phase 19F NMR Spectroscopy to develop conditions for solid-phase synthesis of two libraries of pilicides, i.e. compounds designed to inhibit assembly of adhesive pili in uropathogenic Escherichia coli. Attachment to and cleavage from the linker could be monitored based on the chemical shift of the fluorine atom of the linker. In addition, use of the linker as internal standard allowed quantification and optimization of reactions occurring further away from the linker when fluorinated building blocks were employed. Importantly, high-quality 19F NMR spectra were obtained for compounds linked to a TentaGel resin in a standard NMR tube using an ordinary NMR instrument.
Mikael Elofsson - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and evaluation of 2-(2-fluoro-4-hydroxymethyl-5-methoxy-phenoxy)acetic acid as a linker in solid-phase synthesis monitored by gel-phase 19F NMR Spectroscopy
Organic & biomolecular chemistry, 2007Co-Authors: Fredrik K. Wallner, Sara Spjut, Dan Boström, Mikael ElofssonAbstract:Gel-phase 19F NMR Spectroscopy is a useful monitoring technique for solid-phase organic chemistry due to the high information content it delivers and swift acquisition times, using standard NMR spectrometers. This paper describes the synthesis of the novel linker 2-(2-fluoro-4-hydroxymethyl-5-methoxy-phenoxy)acetic acid in 29% yield over seven steps, using nucleophilic aromatic substitutions on 2,4,5-trifluorobenzonitrile as key steps. Following standard solid-phase synthesis a peptide could be cleaved from the linker using 20% TFA in CH2Cl2 in 30 minutes, in contrast to a previously described monoalkoxy linker that requires 90% TFA in water at elevated temperature. A resin-bound peptide could be successfully glycosylated using only two equivalents of a thioglycoside donor, activated with N-iodosuccinimide and trifluoromethanesulfonic acid, and subsequent cleavage and deprotection gave the target glycopeptide. Direct glycosylation of the linker itself followed by mild acidic cleavage gave a fully protected hemiacetal for further chemical manipulation.
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Solid-Phase Synthesis of α-Gal Epitopes: On-Resin Analysis of Solid-Phase Oligosaccharide Synthesis with 19F NMR Spectroscopy
The Journal of organic chemistry, 2003Co-Authors: Mickael Mogemark, Mikael Elofsson, Jan KihlbergAbstract:A route for solid-phase synthesis of the α-Gal epitopes Gal(α1−3)Gal(β1−4)Glc and Gal(α1−3)Gal(β1−4)GlcNAc is described. These trisaccharide antigens are responsible for hyperacute rejection in xenotransplantation of porcine organs. Optimization of the solid-phase synthesis relied on use of fluorinated protective groups for the carbohydrate building blocks and use of a fluorinated linker. This allowed convenient on-resin analysis of the reactions with gel-phase 19F NMR Spectroscopy. Conditions were established which allowed reductive ring-opening of 4,6-O-benzylidene acetals to be performed on the solid phase with high regioselectivity to furnish the corresponding 6-O-benzyl ethers. It was found that glycosylations could be conveniently carried out by using thioglycosides as donors with N-iodosuccinimide and trifluoromethanesulfonic acid as the promoter system. With use of these conditions a challenging α-glycosidic linkage was successfully installed with complete stereoselectivity in the final glycosylat...
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Fluorinated protective groups for on-resin quantification of solid-phase oligosaccharide synthesis with 19F NMR Spectroscopy.
Chembiochem : a European journal of chemical biology, 2002Co-Authors: Mickael Mogemark, Mikael Elofsson, Jan KihlbergAbstract:Fluorinated Protective Groups for On-Resin Quantification of Solid- Phase Oligosaccharide Synthesis with 19F NMR Spectroscopy
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Monitoring Solid-Phase Glycoside Synthesis with 19F NMR Spectroscopy
Organic letters, 2001Co-Authors: Mickael Mogemark, Mikael Elofsson, Jan KihlbergAbstract:A simple and efficient method for monitoring and optimizing carbohydrate synthesis on polymeric support by using 19F NMR Spectroscopy is described. The method relies on the use of fluorinated variants of protective groups that are in common use in oligosaccharide synthesis.
Mickael Mogemark - One of the best experts on this subject based on the ideXlab platform.
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Solid-phase glycoconjugate synthesis : on-resin analysis with gel-phase ¹9F NMR Spectroscopy
2005Co-Authors: Mickael MogemarkAbstract:An efficient and versatile non-destructive method to analyze the progress of solid-phase glycoconjugate synthesis with gel-phase 19F NMR Spectroscopy is described. The method relies on use of fluor ...
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Solid-Phase Synthesis of α-Gal Epitopes: On-Resin Analysis of Solid-Phase Oligosaccharide Synthesis with 19F NMR Spectroscopy
The Journal of organic chemistry, 2003Co-Authors: Mickael Mogemark, Mikael Elofsson, Jan KihlbergAbstract:A route for solid-phase synthesis of the α-Gal epitopes Gal(α1−3)Gal(β1−4)Glc and Gal(α1−3)Gal(β1−4)GlcNAc is described. These trisaccharide antigens are responsible for hyperacute rejection in xenotransplantation of porcine organs. Optimization of the solid-phase synthesis relied on use of fluorinated protective groups for the carbohydrate building blocks and use of a fluorinated linker. This allowed convenient on-resin analysis of the reactions with gel-phase 19F NMR Spectroscopy. Conditions were established which allowed reductive ring-opening of 4,6-O-benzylidene acetals to be performed on the solid phase with high regioselectivity to furnish the corresponding 6-O-benzyl ethers. It was found that glycosylations could be conveniently carried out by using thioglycosides as donors with N-iodosuccinimide and trifluoromethanesulfonic acid as the promoter system. With use of these conditions a challenging α-glycosidic linkage was successfully installed with complete stereoselectivity in the final glycosylat...
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Fluorinated protective groups for on-resin quantification of solid-phase oligosaccharide synthesis with 19F NMR Spectroscopy.
Chembiochem : a European journal of chemical biology, 2002Co-Authors: Mickael Mogemark, Mikael Elofsson, Jan KihlbergAbstract:Fluorinated Protective Groups for On-Resin Quantification of Solid- Phase Oligosaccharide Synthesis with 19F NMR Spectroscopy
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Monitoring Solid-Phase Glycoside Synthesis with 19F NMR Spectroscopy
Organic letters, 2001Co-Authors: Mickael Mogemark, Mikael Elofsson, Jan KihlbergAbstract:A simple and efficient method for monitoring and optimizing carbohydrate synthesis on polymeric support by using 19F NMR Spectroscopy is described. The method relies on the use of fluorinated variants of protective groups that are in common use in oligosaccharide synthesis.
Anette Svensson - One of the best experts on this subject based on the ideXlab platform.
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Preparation of fluorinated linkers: use of 19F NMR Spectroscopy to establish conditions for solid-phase synthesis of pilicide libraries.
Journal of combinatorial chemistry, 2000Co-Authors: Anette Svensson, Tomas Fex, Jan KihlbergAbstract:Three fluorinated linkers which are analogues of linkers commonly used in solid-phase peptide synthesis have been prepared. One of the linkers was used in combination with gel-phase 19F NMR Spectroscopy to develop conditions for solid-phase synthesis of two libraries of pilicides, i.e. compounds designed to inhibit assembly of adhesive pili in uropathogenic Escherichia coli. Attachment to and cleavage from the linker could be monitored based on the chemical shift of the fluorine atom of the linker. In addition, use of the linker as internal standard allowed quantification and optimization of reactions occurring further away from the linker when fluorinated building blocks were employed. Importantly, high-quality 19F NMR spectra were obtained for compounds linked to a TentaGel resin in a standard NMR tube using an ordinary NMR instrument.
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Fluorinated linkers for monitoring solid-phase synthesis using gel-phase 19F NMR Spectroscopy
Tetrahedron Letters, 1998Co-Authors: Anette Svensson, Tomas Fex, Karl-erik Bergquist, Jan KihlbergAbstract:Abstract Three fluorinated linkers which are analogues of linkers commonly used in solid-phase peptide synthesis have been prepared. Using 19F NMR Spectroscopy, the fluorine atom of the linker allowed monitoring of several transformations in the solid-phase synthesis of a peptoid having a coumarin moiety. Especially, attachment of the linker to the solid phase, coupling of the first building block to the linker and cleavage of the product were efficiently monitored and optimised.
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Use of 19F NMR Spectroscopy to evaluate reactions in solid phase organic synthesis
Tetrahedron Letters, 1996Co-Authors: Anette Svensson, Tomas Fex, Jan KihlbergAbstract:Abstract Gel-phase 19F NMR Spectroscopy has been used to characterize products from a variety of reactions of fluorinated aromatics linked to a TentaGel resin. High quality spectra were obtained in a few minutes using an ordinary NMR spectrometer, and the 19F chemical shifts of the support-bound compounds closely matched those of soluble references. In addition, substantial chemical shift differences were obtained for almost all of the synthetic transformations, illustrating the potential of 19F NMR for rapid monitoring of reactions in solid-phase organic synthesis.
Jeremy K. Nicholson - One of the best experts on this subject based on the ideXlab platform.
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Metabolism of 2-fluoro-4-iodoaniline in earthworm Eisenia veneta using 19F-NMR Spectroscopy, HPLC-MS, and HPLC-ICPMS (127I)
Xenobiotica; the fate of foreign compounds in biological systems, 2007Co-Authors: Catherine J. Duckett, John C Lindon, Ian D Wilson, Heather Walker, Fadi Abou-shakra, David Douce, Jeremy K. NicholsonAbstract:A combination of 19F-NMR Spectroscopy, HPLC-MS/MS, HPLC-MS with constant neutral loss scanning of 127, and HPLC-ICPMS with iodine detection has enabled the profiling, quantification, and limited characterization of the metabolites produced in the earthworm Eisenia veneta, following exposure to 2-fluoro-4-iodoaniline. Mass spectrometric analysis of the worm tissue and coelomic fluid afforded the identification of two Phase II metabolites, N-glutamyl and N-glucoside conjugates, indicating the importance of these pathways in the detoxification of xenobiotics for earthworms. Several further metabolites were observed and quantified by 19F-NMR Spectroscopy and HPLC-127I-ICPMS, although these were of low abundance and their structures were not unequivocally identified. The parent compound and the glutamyl conjugate were found to be the major xenobiotic components of both the coelomic fluid and the worm tissue, representing approximately 23 and approximately 35%, respectively, of the dose that was recovered from ...
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Metabolism of 3-chloro-4-fluoroaniline in rat using [14C]-radiolabelling, 19F-NMR Spectroscopy, HPLC-MS/MS, HPLC-ICPMS and HPLC-NMR
Xenobiotica; the fate of foreign compounds in biological systems, 2006Co-Authors: Catherine J. Duckett, John C Lindon, Ian D Wilson, Heather Walker, Fadi Abou-shakra, Jeremy K. NicholsonAbstract:The metabolic fate of 3-chloro-4-fluoroaniline was investigated in rat following intraperitoneal (i.p.) administration at 5 and 50 mg kg−1 using a combination of HPLC-MS, HPLC-MS/MS, 19F-NMR Spectroscopy, HPLC-NMR Spectroscopy and high-pressure liquid chromatography-inductively coupled plasma mass spectrometry (HPLC-ICPMS) with 35Cl and 34S detection. The metabolism of 3-chloro-4-fluoroaniline at both doses was rapid and extensive, to a large number of metabolites, with little unchanged compound excreted via the urine. Dosing at 5 mg kg−1 with [14C]-labelled compound enabled the comparison of standard radioassay analysis methods with 19F-NMR Spectroscopy. 19F-NMR resonances were only readily detectable in the 0–12 h post-dose samples. Dosing at 50 mg kg−1 allowed the facile and specific detection and quantification of metabolites by 19F-NMR Spectroscopy. Metabolite profiling was also possible at this dose level using HPLC-ICPMS with 35Cl-specific detection. The principal metabolites of 3-chloro-4-fluoroan...
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The potential of 19F NMR Spectroscopy for rapid screening of cell cultures for models of mammalian drug metabolism.
The Analyst, 2001Co-Authors: Olivia Corcoran, John C Lindon, Richard M. Hall, Ismail M. Ismail, Jeremy K. NicholsonAbstract:The use of microbial cultures as a complementary model for mammalian drug metabolism has been well established previously. Here is a preliminary investigation into the potential of 19F NMR Spectroscopy as a rapid screening tool to quantify the biotransformations of fluorine-containing model drugs. Biotransformations of three model drugs in 48 taxonomically diverse organisms were measured by acquiring 19F NMR spectra at 376 MHz. The presence of fluorine in the molecules allowed rapid, simultaneous detection of over 20 biotransformation products without sample pre-treatment, chromatography, mass spectrometric techniques or the use of radiolabelled substrates. The detection limit at 376 MHz using 5 mm NMR tubes was ca. 0.3 μg ml−1 using a typical analysis time of 20 min per sample. With the recent advent of flow injection NMR technology, analysis time of 5 min could be achieved with less sample. This approach may be used to develop fast small-scale microbial screens for the biosynthesis of metabolite standards and production of novel drug analogues, whilst also having a role in reducing animal experiments needed to identify animal and human metabolites of fluorinated xenobiotics.
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Rapid multi-component detection of fluorinated drug metabolites in whole urine from a ‘cassette’ dose study using high resolution 19F NMR Spectroscopy
Analytical Communications, 1999Co-Authors: Olivia Corcoran, Jeremy K. Nicholson, Ian D WilsonAbstract:High resolution 19F NMR Spectroscopy has been successfully applied to the analysis of drug metabolites in whole rat urine from a ‘cassette’ dose study of 6 fluorinated test compounds dosed at 10 mg kg–1 per compound. A total of 21 compound-related molecules were rapidly detected in the 0–8 h urine samples. The metabolic fate of the compounds after cassette administration appeared to be the same as when the compounds were dosed individually. 19F NMR may thus enable metabolism to be estimated for several compounds simultaneously, with minimal sample preparation, and without interference from endogenous molecules in the biofluid. This analytical approach may therefore be of value at the drug discovery stage in the development of ‘high throughput’ in vivo metabolic screens.
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Degradation of 4-fluorobiphenyl in soil investigated by 19F NMR Spectroscopy and 14C radiolabelling analysis.
Chemosphere, 1999Co-Authors: N.a. Green, Andrew A. Meharg, C. Till, J. Troke, Jeremy K. NicholsonAbstract:Abstract The incubation of the model pollutant [U-14C]′-4-fluorobiphenyl (4FBP) in soil, in the presence and absence of biphenyl (a co-substrate), was carried out in order to study the qualitative disposition and fate of the compound using 14C-HPLC and 19F NMR Spectroscopy. Components accounted for using the radiolabel were volatilisation, CO2 evolution, organic solvent extractable and bound residue. Quantitative analysis of these data gave a complete mass balance. After sample preparation, 14C-HPLC was used to establish the number of 4FBP related components present in the organic solvent extract. 19F NMR was also used to quantify the organic extracts and to identify the components of the extract. Both approaches showed that the composition of the solvent extractable fractions comprised only parent compound with no metabolites present. As the 14C radiolabel was found to be incorporated into the soil organic matter this indicates that metabolites were being generated, but were highly transitory as incorporation into the SOM was rapid. The inclusion of the co-substrate biphenyl was to increase the overall rate of degradation of 4FBP in soil. The kinetics of disappearance of parent from the soil using the data obtained were investigated from both techniques. This is the first report describing the degradation of a fluorinated biphenyl in soil.
