The Experts below are selected from a list of 279 Experts worldwide ranked by ideXlab platform
Jill Barber - One of the best experts on this subject based on the ideXlab platform.
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Mechanism for the Degradation of Erythromycin A and Erythromycin A 2‘-Ethyl Succinate in Acidic Aqueous Solution
Journal of Physical Chemistry A, 2007Co-Authors: Abdolreza Hassanzadeh, Jill Barber, Gareth A. Morris, Peter A. GorryAbstract:A major drawback of the antibiotic erythromycin A is its extreme acid sensitivity, leading to rapid inactivation in the stomach. The accepted model for degradation in aqueous acidic solution has erythromycin A in equilibrium with erythromycin A enol ether and degrading to anhydroerythromycin A. We report a detailed kinetic study of the acidic degradation of erythromycin A and of erythromycin A 2‘-ethyl succinate (the market-leading pediatric prodrug), investigating the reaction rates and degradation products via NMR. This reveals that the accepted mechanism is incorrect and that both the enol ether and the anhydride are in equilibrium with the parent erythromycin. By implication, both the anhydride and enol ether are antibacterially inactive reservoirs for the parent erythromycin. The actual degradation pathway is the slow loss of Cladinose from erythromycin A (or erythromycin A 2‘-ethyl succinate), which is reported here for the first time in a kinetic study. The kinetic analysis is based on global, nonl...
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Mechanism for the Degradation of Erythromycin A and Erythromycin A 2‘-Ethyl Succinate in Acidic Aqueous Solution
The journal of physical chemistry. A, 2007Co-Authors: Abdolreza Hassanzadeh, Jill Barber, Gareth A. Morris, Peter A. GorryAbstract:A major drawback of the antibiotic erythromycin A is its extreme acid sensitivity, leading to rapid inactivation in the stomach. The accepted model for degradation in aqueous acidic solution has erythromycin A in equilibrium with erythromycin A enol ether and degrading to anhydroerythromycin A. We report a detailed kinetic study of the acidic degradation of erythromycin A and of erythromycin A 2'-ethyl succinate (the market-leading pediatric prodrug), investigating the reaction rates and degradation products via NMR. This reveals that the accepted mechanism is incorrect and that both the enol ether and the anhydride are in equilibrium with the parent erythromycin. By implication, both the anhydride and enol ether are antibacterially inactive reservoirs for the parent erythromycin. The actual degradation pathway is the slow loss of Cladinose from erythromycin A (or erythromycin A 2'-ethyl succinate), which is reported here for the first time in a kinetic study. The kinetic analysis is based on global, nonlinear, simultaneous least-squares fitting of time course concentrations for all species across multiple datasets to integrated rate expressions, to provide robust estimates of the rate constants.
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Systematic approach to understanding macrolide-ribosome interactions: NMR and modeling studies of oleandomycin and its derivatives
The journal of physical chemistry. A, 2006Co-Authors: Predrag Novak, Predrag Tepeš, Iva Tatić, Sanja Koštrun, Jill BarberAbstract:The three-dimensional structures of oleandomycin (1) and its derivatives oleandomycin-9-oxime (2) and 10,11-anhydrooleandomycin (3) were determined in different solvents by the combined use of NMR and molecular modeling methods. The experimental NMR data were compared with the results of molecular modeling and known crystal structures of the related molecules. It was shown that the dominant conformation of the lactone ring is the folded-out conformation with some amounts of the folded-in one depending on the solvent and temperature, while desosamine and Cladinose sugars adopt the usual chair conformations. Modeling calculations provided evidence for conformational changes in the upper lactone region as well. Saturation transfer difference (STD) NMR experiments have provided information on the binding epitopes of 1-3 in complexes with E. coli ribosomes. The obtained molecular surfaces in close contact with ribosomes were compared with recently available 3D structures of the related macrolide-ribosome complexes, and the observed differences were discussed. The knowledge gained from this study can serve as a platform for the design of novel macrolides with an improved biological profile.
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A Systematic Approach to Understanding Ribosome-Macrolide Interactions: NMR and Modeling Studies of Oleandomycin and Its Derivatives
Journal of Physical Chemistry A, 2006Co-Authors: Predrag Novak, Predrag Tepeš, Iva Tatić, Sanja Koštrun, Jill BarberAbstract:The three-dimensional structures of oleandomycin (1) and its derivatives oleandomycin-9-oxime (2) and 10, 11- anhydrooleandomycin (3) were determined in different solvents by the combined use of NMR and molecular modeling methods. The experimental NMR data were compared with the results of molecular modeling and known crystal structures of the related molecules. It was shown that the dominant conformation of the lactone ring is the folded-out conformation with some amounts of the folded-in one depending on the solvent and temperature, while desosamine and Cladinose sugars adopt the usual chair conformations. Modeling calculations provided evidence for conformational changes in the upper lactone region as well. Saturation transfer difference (STD) NMR experiments have provided information on the binding epitopes of 1-3 in complexes with E. coli ribosomes. The obtained molecular surfaces in close contact with ribosomes were compared with recently available 3D structures of the related macrolide-ribosome complexes, and the observed differences were discussed. The knowledge gained from this study can serve as a platform for the design of novel macrolides with an improved
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Acid-catalyzed degradation of clarithromycin and erythromycin B: a comparative study using NMR spectroscopy.
Journal of medicinal chemistry, 2000Co-Authors: Mohd Nizam Mordi, Gareth A. Morris, Michelle D. Pelta, Valerie Boote, Jill BarberAbstract:One of the major drawbacks in the use of the antibiotic erythromycin A is its extreme acid sensitivity, leading to degradation in the stomach following oral administration. The modern derivative clarithromycin degrades by a different mechanism and much more slowly. We have studied the pathway and kinetics of the acid-catalyzed degradation of clarithromycin and of erythromycin B, a biosynthetic precursor of erythromycin A which also has good antibacterial activity, using 1H NMR spectroscopy. Both drugs degrade by loss of the Cladinose sugar ring and with similar rates of reaction. These results suggest that erythromycin B has potential as an independent therapeutic entity, with superior acid stability compared with erythromycin A and with the advantage over clarithromycin of being a natural product.
Predrag Novak - One of the best experts on this subject based on the ideXlab platform.
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Epitope Mapping of Macrolide Antibiotics to Bovine Serum Albumin by Saturation Transfer Difference NMR Spectroscopy
Croatica Chemica Acta, 2007Co-Authors: Predrag Novak, Predrag Tepeš, Vedrana LazićAbstract:Saturation transfer difference NMR spectroscopy was employed to characterize epitopes of macrolide antibiotics, azithromycin, oleandomycin and telithromycin binding to bovine serum albumin. The structural parts of azithromycin and oleandomycin in intimate contact with bovine serum albumin were found to be similar while those of telithromycin showed similarities but also some differences. The latter were mostly due to different structural elements of antibiotics that interact with the protein, especially the alkyl-heteroaryl side chain in telithromycin and Cladinose and desosamine sugars in azithromycin and oleandomycin. The epitope maps as determined in this study can contribute to better understanding of the overall bioactivity of macrolides.
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Epitope Mapping of Macrolide Antibiotics to Bovine Serum Albumin by Saturation Transfer Difference NMR Spectroscopy*
2007Co-Authors: Predrag Novak, Predrag TepeAbstract:Saturation transfer difference NMR spectroscopy was employed to characterize epitopes of macrolide antibiotics, azithromycin, oleandomycin and telithromycin binding to bovine serum albumin. The structural parts of azithromycin and oleandomycin in intimate contact with bo-vine serum albumin were found to be similar while those of telithromycin showed similarities but also some differences. The latter were mostly due to different structural elements of antibi-otics that interact with the protein, especially the alkyl-heteroaryl side chain in telithromycin and Cladinose and desosamine sugars in azithromycin and oleandomycin. The epitope maps as determined in this study can contribute to better understanding of the overall bioactivity of macrolides. Keywords: STD NMR spectroscopy macrolide antibiotics albumin epitope mapping * Dedicated to Professor Haruo Hosoya in happy celebration of his 70th birthday
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Systematic approach to understanding macrolide-ribosome interactions: NMR and modeling studies of oleandomycin and its derivatives
The journal of physical chemistry. A, 2006Co-Authors: Predrag Novak, Predrag Tepeš, Iva Tatić, Sanja Koštrun, Jill BarberAbstract:The three-dimensional structures of oleandomycin (1) and its derivatives oleandomycin-9-oxime (2) and 10,11-anhydrooleandomycin (3) were determined in different solvents by the combined use of NMR and molecular modeling methods. The experimental NMR data were compared with the results of molecular modeling and known crystal structures of the related molecules. It was shown that the dominant conformation of the lactone ring is the folded-out conformation with some amounts of the folded-in one depending on the solvent and temperature, while desosamine and Cladinose sugars adopt the usual chair conformations. Modeling calculations provided evidence for conformational changes in the upper lactone region as well. Saturation transfer difference (STD) NMR experiments have provided information on the binding epitopes of 1-3 in complexes with E. coli ribosomes. The obtained molecular surfaces in close contact with ribosomes were compared with recently available 3D structures of the related macrolide-ribosome complexes, and the observed differences were discussed. The knowledge gained from this study can serve as a platform for the design of novel macrolides with an improved biological profile.
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A Systematic Approach to Understanding Ribosome-Macrolide Interactions: NMR and Modeling Studies of Oleandomycin and Its Derivatives
Journal of Physical Chemistry A, 2006Co-Authors: Predrag Novak, Predrag Tepeš, Iva Tatić, Sanja Koštrun, Jill BarberAbstract:The three-dimensional structures of oleandomycin (1) and its derivatives oleandomycin-9-oxime (2) and 10, 11- anhydrooleandomycin (3) were determined in different solvents by the combined use of NMR and molecular modeling methods. The experimental NMR data were compared with the results of molecular modeling and known crystal structures of the related molecules. It was shown that the dominant conformation of the lactone ring is the folded-out conformation with some amounts of the folded-in one depending on the solvent and temperature, while desosamine and Cladinose sugars adopt the usual chair conformations. Modeling calculations provided evidence for conformational changes in the upper lactone region as well. Saturation transfer difference (STD) NMR experiments have provided information on the binding epitopes of 1-3 in complexes with E. coli ribosomes. The obtained molecular surfaces in close contact with ribosomes were compared with recently available 3D structures of the related macrolide-ribosome complexes, and the observed differences were discussed. The knowledge gained from this study can serve as a platform for the design of novel macrolides with an improved
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CCA-2735 Original Scientific Paper Conformational Behaviour of 11-O-Methylazithromycin in the Solid and Solution State
2000Co-Authors: Dijana A Matak-vinkovi, Predrag Novak, Mladen A Vinkovi, Gabrijela B Kobrehel, Gorjana LazarevskicAbstract:Conformational behaviour of azithromycin 11-OMe derivative 2 (Scheme 1) has been studied in the solid and solution state. In the CDCl3 and DMSO solution, 2 mainly adopts the »folded-in « confor-mation. 11-OMe group is oriented toward the centre of aglycone ring. The crystal structure of DMSO solvate of 2 has been solved by the molecular replacement method using the solution state confor-mation as the search model. Conformation of 2 in the solid and so-lution state is very similar. Molecules of 2 are held together in the crystal by van der Waals interactions, forming a solvent channel along the b axis. The DMSO molecule is found to be disordered and bound to Cladinose moiety of 2 by H-bond O4"-H...O1s. Key words: azithromycin, crystal structure, molecular replacement, NMR
Peter A. Gorry - One of the best experts on this subject based on the ideXlab platform.
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Mechanism for the Degradation of Erythromycin A and Erythromycin A 2‘-Ethyl Succinate in Acidic Aqueous Solution
Journal of Physical Chemistry A, 2007Co-Authors: Abdolreza Hassanzadeh, Jill Barber, Gareth A. Morris, Peter A. GorryAbstract:A major drawback of the antibiotic erythromycin A is its extreme acid sensitivity, leading to rapid inactivation in the stomach. The accepted model for degradation in aqueous acidic solution has erythromycin A in equilibrium with erythromycin A enol ether and degrading to anhydroerythromycin A. We report a detailed kinetic study of the acidic degradation of erythromycin A and of erythromycin A 2‘-ethyl succinate (the market-leading pediatric prodrug), investigating the reaction rates and degradation products via NMR. This reveals that the accepted mechanism is incorrect and that both the enol ether and the anhydride are in equilibrium with the parent erythromycin. By implication, both the anhydride and enol ether are antibacterially inactive reservoirs for the parent erythromycin. The actual degradation pathway is the slow loss of Cladinose from erythromycin A (or erythromycin A 2‘-ethyl succinate), which is reported here for the first time in a kinetic study. The kinetic analysis is based on global, nonl...
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Mechanism for the Degradation of Erythromycin A and Erythromycin A 2‘-Ethyl Succinate in Acidic Aqueous Solution
The journal of physical chemistry. A, 2007Co-Authors: Abdolreza Hassanzadeh, Jill Barber, Gareth A. Morris, Peter A. GorryAbstract:A major drawback of the antibiotic erythromycin A is its extreme acid sensitivity, leading to rapid inactivation in the stomach. The accepted model for degradation in aqueous acidic solution has erythromycin A in equilibrium with erythromycin A enol ether and degrading to anhydroerythromycin A. We report a detailed kinetic study of the acidic degradation of erythromycin A and of erythromycin A 2'-ethyl succinate (the market-leading pediatric prodrug), investigating the reaction rates and degradation products via NMR. This reveals that the accepted mechanism is incorrect and that both the enol ether and the anhydride are in equilibrium with the parent erythromycin. By implication, both the anhydride and enol ether are antibacterially inactive reservoirs for the parent erythromycin. The actual degradation pathway is the slow loss of Cladinose from erythromycin A (or erythromycin A 2'-ethyl succinate), which is reported here for the first time in a kinetic study. The kinetic analysis is based on global, nonlinear, simultaneous least-squares fitting of time course concentrations for all species across multiple datasets to integrated rate expressions, to provide robust estimates of the rate constants.
Gareth A. Morris - One of the best experts on this subject based on the ideXlab platform.
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Mechanism for the Degradation of Erythromycin A and Erythromycin A 2‘-Ethyl Succinate in Acidic Aqueous Solution
Journal of Physical Chemistry A, 2007Co-Authors: Abdolreza Hassanzadeh, Jill Barber, Gareth A. Morris, Peter A. GorryAbstract:A major drawback of the antibiotic erythromycin A is its extreme acid sensitivity, leading to rapid inactivation in the stomach. The accepted model for degradation in aqueous acidic solution has erythromycin A in equilibrium with erythromycin A enol ether and degrading to anhydroerythromycin A. We report a detailed kinetic study of the acidic degradation of erythromycin A and of erythromycin A 2‘-ethyl succinate (the market-leading pediatric prodrug), investigating the reaction rates and degradation products via NMR. This reveals that the accepted mechanism is incorrect and that both the enol ether and the anhydride are in equilibrium with the parent erythromycin. By implication, both the anhydride and enol ether are antibacterially inactive reservoirs for the parent erythromycin. The actual degradation pathway is the slow loss of Cladinose from erythromycin A (or erythromycin A 2‘-ethyl succinate), which is reported here for the first time in a kinetic study. The kinetic analysis is based on global, nonl...
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Mechanism for the Degradation of Erythromycin A and Erythromycin A 2‘-Ethyl Succinate in Acidic Aqueous Solution
The journal of physical chemistry. A, 2007Co-Authors: Abdolreza Hassanzadeh, Jill Barber, Gareth A. Morris, Peter A. GorryAbstract:A major drawback of the antibiotic erythromycin A is its extreme acid sensitivity, leading to rapid inactivation in the stomach. The accepted model for degradation in aqueous acidic solution has erythromycin A in equilibrium with erythromycin A enol ether and degrading to anhydroerythromycin A. We report a detailed kinetic study of the acidic degradation of erythromycin A and of erythromycin A 2'-ethyl succinate (the market-leading pediatric prodrug), investigating the reaction rates and degradation products via NMR. This reveals that the accepted mechanism is incorrect and that both the enol ether and the anhydride are in equilibrium with the parent erythromycin. By implication, both the anhydride and enol ether are antibacterially inactive reservoirs for the parent erythromycin. The actual degradation pathway is the slow loss of Cladinose from erythromycin A (or erythromycin A 2'-ethyl succinate), which is reported here for the first time in a kinetic study. The kinetic analysis is based on global, nonlinear, simultaneous least-squares fitting of time course concentrations for all species across multiple datasets to integrated rate expressions, to provide robust estimates of the rate constants.
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Acid-catalyzed degradation of clarithromycin and erythromycin B: a comparative study using NMR spectroscopy.
Journal of medicinal chemistry, 2000Co-Authors: Mohd Nizam Mordi, Gareth A. Morris, Michelle D. Pelta, Valerie Boote, Jill BarberAbstract:One of the major drawbacks in the use of the antibiotic erythromycin A is its extreme acid sensitivity, leading to degradation in the stomach following oral administration. The modern derivative clarithromycin degrades by a different mechanism and much more slowly. We have studied the pathway and kinetics of the acid-catalyzed degradation of clarithromycin and of erythromycin B, a biosynthetic precursor of erythromycin A which also has good antibacterial activity, using 1H NMR spectroscopy. Both drugs degrade by loss of the Cladinose sugar ring and with similar rates of reaction. These results suggest that erythromycin B has potential as an independent therapeutic entity, with superior acid stability compared with erythromycin A and with the advantage over clarithromycin of being a natural product.
Jean-pierre Girault - One of the best experts on this subject based on the ideXlab platform.
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conformational analysis of ketolide conformations of ru 004 in solution and bound to bacterial ribosomes
Journal of Medicinal Chemistry, 1998Co-Authors: Gildas Bertho, Marcel Delaforge, Josyane Gharbibenarous, Catherine Lang, And Annick Parent, Jean-pierre GiraultAbstract:A new structurally distinct class of 14-membered-ring macrolides is characterized by a keto-function instead of the Cladinose sugar, well-known for its fragility even in weakly acidic media. This n...
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Conformational change due to esterification of hydroxy groups in erythromycin A and its major metabolite: Analysis of these derivatives with different biological properties using NMR and Molecular Dynamics (MD) data
Bioorganic & medicinal chemistry, 1995Co-Authors: Patrick Ladam, Josyane Gharbi-benarous, Marcel Delaforge, Marie-rose Van Calsteren, C. K. Jankowski, Jean-pierre GiraultAbstract:A conformational study is performed on the acylated erythromycin and erythralosamine derivatives from comparison between experimental results (NMR) and theoretical calculations by Molecular Dynamics (MD) in attempts to correlate their conformations with their abilities to generate cytochrome P450-nitroso metabolite complexes in vitro. As the 3′-dimethyl-amino function of the desosamine is metabolized and responsible for the interaction with cytochrome P450, its position, mobility and steric hindrance in the proximity of this functional group are related to its biological properties. The major conformations of the lactone ring were termed A (A1, A2, A3) and B (B1, B2), and this macrocycle flexibility induced five different orientations a, b, c, d and e for the desosamine sugar. Conformations A and B differ in many ways but the major change is the inward folding of the C(3) fragment in B. Conformer a exhibits an orientation of the desosamine nearly perpendicular to the macrocycle whereas the two units are in the same plane in conformations c and e. For conformation b, the Cladinose unit lifts up above the macrocycle. Conformation d exhibits a turned-back Cladinose. In the erythromycin derivatives esterification at the β position to the N(CH3)2 group of the desosamine reduces the degree of freedom of the macrocyclic lactone ring which corresponds to conformation A only. The desosamine sugar was found to be perpendicular to the macrocycle (a conformer) and both sugar groups are parallel to reduce the steric energy. In the erythralosamine derivatives, the macrocycle is always present as conformation B with the two conformations b and c of the sugar rings. The steric parameters favour the b conformers in which the amino group is tilted up, while in 3,2′-dibenzoylated stacking aromatic attraction stabilizes the planar c conformer. Both isomers are thus shown to adopt well-defined conformations and to be well-adapted for a comparative structure-activity correlation studies. There is a significant relationship between the conformation b and the formation of cytochrome P450-nitroso metabolite complexes.
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A comparative NMR study between the macrolide antibiotic roxithromycin and erythromycin A with different biological properties.
Journal of medicinal chemistry, 1991Co-Authors: Josyane Gharbi-benarous, Marcel Delaforge, C. K. Jankowski, Jean-pierre GiraultAbstract:1H nuclear Overhauser enhancement studies and 1H NMR 3J analysis establish the similarity between the major solution-state conformation of roxithromycin (1) and the erythromycin (2). A major difference between the structure of antibiotics 1 and 2 is the replacement of the 9-keto group in 2 by a 9-[O-(2,5-dioxahexyl)oxime] group. The NOE studies show that this oxime chain is oriented above the macrocyclic lactone ring and that the oxygen atoms of this chain are engaged in tight hydrogen bonding with a water molecule and with the 6- and 11-hydroxyl groups of the macrocycle. It results in a globular form of the whole roxithromycin molecule. These data explain also a relative hydrophobicity of this antibiotic. Erythromycin A (2), which presents a less rigid macrocycle with two free hydroxyl groups (6-OH and 11-OH), forms a dimer detected by FAB mass spectroscopy. 1H and 13C NMR relaxation measurements (T1) for both antibiotics show that interresidue hydrogen bonds in roxithromycin reduce the rotational freedom of the macrocyclic lactone ring and consequently the motions of desosamine and Cladinose sugars. In another way, an ionization of the amino function occurs in the various media according to the nature of the antibiotic. This would allow the reactivity modification of the desosamine unit. In the biological study, the modifications of the 455-nm metabolite-cytochrome P-450 complex formation are observed.