- Structure-activity relationships of glycogen phosphorylase inhibitor FR258900 and its analogues: A combined synthetic, enzyme kinetics, and computational study
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A series of O- or N-cinnamoylated, p-coumaroylated, feruloylated, phenyl, and substituted phenylpropiolated derivatives of lmalic, 3-hydroxypentanedioic, and l-glutamic acids were synthesized as analogues of the natural product glycogen phosphorylase (GP) inhibitor FR258900 (2,3-bis(4-hydroxycinnamoyloxy) glutaric acid). These compounds proved practically inactive against rabbit muscle glycogen phosphorylase b. A structure-activity study involving previously synthesized tartaric acid analogues of FR258900 revealed that two acyl moieties must be present in the compounds to make a good inhibitor. Molecular modeling methods (docking and quantitative structure-activity relationship (QSAR) calculations) were used to understand the nature of the binding affinities of these GP inhibitors. The generated 3D models for GP-inhibitor complexes showed that both the polar allosteric site pocket and the hydrophobic pocket at the interface of the homodimeric units of GP were important for effective binding of the acyl and aromatic moieties of the inhibitors. The predictive QSAR models consist of empirical and quantum mechanics descriptors and provide good explanatory and predictive abilities (prediction coefficient Q2=0.7-0.9 when cross-validation procedures were performed).
- Juhsz, Lszl,Varga, Gergely,Sztankovics, Andrea,Bke, Ferenc,Docsa, Tibor,Kiss-Szikszai, Attila,Gergely, Pl,Ka, Juraj,Tvaroka, Igor,Somsk, Lszl
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p. 1558 - 1568
(2015/02/05)
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- Structure-Activity Relationships of Glycogen Phosphorylase Inhibitor FR258900 and Its Analogues: A Combined Synthetic, Enzyme Kinetics, and Computational Study
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A series of O- or N-cinnamoylated, p-coumaroylated, feruloylated, phenyl, and substituted phenylpropiolated derivatives of L-malic, 3-hydroxypentanedioic, and L-glutamic acids were synthesized as analogues of the natural product glycogen phosphorylase (GP) inhibitor FR258900 (2,3-bis(4-hydroxycinnamoyloxy)glutaric acid). These compounds proved practically inactive against rabbit muscle glycogen phosphorylase b. A structure-activity study involving previously synthesized tartaric acid analogues of FR258900 revealed that two acyl moieties must be present in the compounds to make a good inhibitor. Molecular modeling methods (docking and quantitative structure-activity relationship (QSAR) calculations) were used to understand the nature of the binding affinities of these GP inhibitors. The generated 3D models for GP-inhibitor complexes showed that both the polar allosteric site pocket and the hydrophobic pocket at the interface of the homodimeric units of GP were important for effective binding of the acyl and aromatic moieties of the inhibitors. The predictive QSAR models consist of empirical and quantum mechanics descriptors and provide good explanatory and predictive abilities (prediction coefficient Q2=0.7-0.9 when cross-validation procedures were performed).
- Juhsz, Lszl,Varga, Gergely,Sztankovics, Andrea,Bke, Ferenc,Docsa, Tibor,Kiss-Szikszai, Attila,Gergely, Pl,Ka, Juraj,Tvaroka, Igor,Somsk, Lszl
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p. 1558 - 1568
(2015/08/24)
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- Amidine dications as superelectrophiles
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2-Dimethylalkylammonium pyridinium and 2-dimethylalkylammonium pyrimidinium ditriflate salts are very powerful methylating agents toward phosphorus (triphenylphosphine) and nitrogen (triethylamine) nucleophiles. In competition experiments with triethylamine as nucleophile, these N-methyl disalts are more reactive methylating agents than dimethyl sulfate. Reaction of the pyridinium dications with water as an oxygen nucleophile leads to attack at the 2-position of the heteroaromatic ring and displacement of an ammonium group; 2-hydroxypyridinium compounds are formed in the first instance, which are easily converted to 2-pyridones. Extending the scope of the reactions, a tricationic 2,6-bis(dimethylalkylammonium) pyridinium salt has also been prepared and characterized and its reactivity as a methylating agent assessed in comparison with that of the dications.
- Corr, Michael J.,Roydhouse, Mark D.,Gibson, Kirsty F.,Zhou, Sheng-Ze,Kennedy, Alan R.,Murphy, John A.
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supporting information; experimental part
p. 17980 - 17985
(2010/04/01)
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- Hydroxydicarboxylic acids: Markers for secondary organic aerosol from the photooxidation of α-pinene
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Detailed organic analysis of fine (PM2.5) rural aerosol collected during summer at K-puszta, Hungary from a mixed deciduous/coniferous forest site shows the presence of polar oxygenated compounds that are also formed in laboratory irradiated α-pinene/NOx/air mixtures. In the present work, two major photooxidation products of α-pinene were characterized as the hydroxydicarboxylic acids, 3-hydroxyglutaric acid, and 2-hydroxy-4-isopropyladipic acid, based on chemical, chromatographic, and mass spectral data. Different types of volatile derivatives, including trimethylsilyl ester/ether, methyl ester trimethylsilyl ether, and ethyl ester trimethylsilyl ether derivatives were measured by gas chromatography/mass spectrometry (GC/MS), and their electron ionization (EI) spectra were interpreted in detail. The proposed structures of the hydroxydicarboxylic acids were confirmed or supported with reference compounds. 2-Hydroxy-4-isopropyladipic acid formally corresponds to a further reaction product of pinic acid involving addition of a molecule of water and opening of the dimethylcyclobutane ring; this proposal is supported by a laboratory irradiation experiment with α-pinene/NOx/air. In addition, we report the presence of a structurally related minor α-pinene photooxidation product, which was tentatively identified as the C7 homolog of 3-hydroxyglutaric acid, 3-hydroxy-4,4-dimethylglutaric acid. The detection of 2-hydroxy-4-isopropyladipic acid in ambient aerosol provides an explanation for the relatively low atmospheric concentrations of pinic acid found during daytime in forest environments.
- Claeys, Magda,Szmigielski, Rafal,Kourtchev, Ivan,Van Der Veken, Pieter,Vermeylen, Reinhilde,Maenhaut, Willy,Jaoui, Mohammed,Kleindienst, Tadeusz E.,Lewandowski, Michael,Offenberg, John H.,Edney, Edward O.
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p. 1628 - 1634
(2007/10/03)
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- Synthesis of macrocyclic polyhydroxy tetralactams derived from L-tartaric acid and β-hydroxyglutaric acid
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The synthesis of new 16-, 18-, 19- or 20-membered secondary tetralactams with L-tartaric acid or β-hydroxyglutaric acid moieties is investigated. The stepwise synthesis with an intermediate diamide diamine provides overall good yields (30-55%) compared with other processes using an intermediate diamide diacid or direct macrocyclization. This synthetic pathway leads to symmetrical or unsymmetrical polyhydroxytetralactams with variable hydroxyl group number. Use of mild acylating agents in this approach allows to avoid the protection-deprotection steps of hydroxyl groups.
- Arnaud, Nathalie,Picard, Claude,Cazaux, Louis,Tisnes, Pierre
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p. 13757 - 13768
(2007/10/03)
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- NMR Investigation of the Thermolysis of Citric Acid
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The thermolytic decomposition of citric acid in the presence of tin/lead solder has been investigated.The solid reaction products were first examined by solid-state 13C NMR.The samples were then dissolved in D2O, and 1H and 13C 1D and 2D (HMQC, TOCSY) spectra were obtained.Results indicate the presence of a series of compounds including 3-hydroxyglutaric, citraconic, itaconic and aconitic acids, and anhydrides.Solution- and solid-state NMR data are provided for citric acid and a number of metal and alkali metal citrate salts.Results of this work are related to the use of citric acid as a solder flux and to the elimination of chlorofluorocarbon cleaning processes in the electronics industry.Index Headings: NMR; Solid-state NMR; Citric acid; Thermolysis.
- Fischer, John W.,Merwin, Lawrence H.,Nissan, Robin A.
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p. 120 - 126
(2007/10/02)
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- Enzymes in Organic Synthesis, 18. Lipase-Catalyzed Asymmetric Alcoholysis of 3-Substituted Pentanedioic Anhydrides
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The influence of several enzymes, alcohols, and solvents on the stereochemical outcome of the asymmetric alcoholysis of 3-substituted pentanedioic anhydrides was investigated.The alcoholysis of 3-acetoxypentanedioic anhydride (5a) in diethyl ether with 2-methylpropanol afforded the (3S)-monoester (S)-6a with an enantiomeric excess of >98percent when the lipase from Candida sp. 382 was used as the enzyme.Under the same conditions, 3-methoxypentanedioic anhydride (5c) was converted by the lipase of Pseudomonas cepacia (Amano PS) into the (3R)-monoester (R)-6c with an e.e. of 90percent.Key Words: Enzymes / Lipases / Pentanedioic anhydrides / Alcoholysis, asymmetric / Pentanedioates
- Ozegowski, Ruediger,Kunath, Annamarie,Schick, Hans
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p. 805 - 808
(2007/10/02)
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