The Experts below are selected from a list of 16119 Experts worldwide ranked by ideXlab platform
D. Christopher Braddock - One of the best experts on this subject based on the ideXlab platform.
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A unifying stereochemical analysis for the formation of halogenated C15-acetogenin medium-ring ethers from Laurencia species via intramolecular bromonium ion assisted epoxide ring-opening and experimental corroboration with a model epoxide.
The Journal of organic chemistry, 2012Co-Authors: Karl J. Bonney, D. Christopher BraddockAbstract:A unifying stereochemical analysis for the formation of the constitutional isomeric halogenated C15-acetogenin medium-ring ether natural products from Laurencia species is presented, where an intramolecular bromonium ion assisted epoxide ring-opening reaction of enantiomerically pure Epoxides can account for ring-size, the position of the halogen substituents, and relative and absolute configurations of the known natural products. Experimentally, a model epoxide corroborates the feasibility of this process for concurrent formation of 7-, 8- and 9-ring ethers corresponding to the halogenated medium-ring ethers of known metabolites from Laurencia species.
Christophe Morisseau - One of the best experts on this subject based on the ideXlab platform.
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substrate and inhibitor selectivity and biological activity of an epoxide hydrolase from trichoderma reesei
Molecular Biology Reports, 2019Co-Authors: Gabriel S De Oliveira, Bruce D. Hammock, Christophe Morisseau, P P Adriani, Felipe S ChambergoAbstract:Epoxide hydrolases (EHs) are present in all living organisms and catalyze the hydrolysis of Epoxides to the corresponding vicinal diols. EH are involved in the metabolism of endogenous and exogenous Epoxides, and thus have application in pharmacology and biotechnology. In this work, we describe the substrates and inhibitors selectivity of an epoxide hydrolase recently cloned from the filamentous fungus Trichoderma reesei QM9414 (TrEH). We also studied the TrEH urea-based inhibitors effects in the fungal growth. TrEH showed high activity on radioative and fluorescent surrogate and natural substrates, especially Epoxides from docosahexaenoic acid. Using a fluorescent surrogate substrate, potent inhibitors of TrEH were identified. Interestingly, one of the best compounds inhibit up to 60% of T. reesei growth, indicating an endogenous role for TrEH. These data make TrEH very attractive for future studies about fungal metabolism of fatty acids and possible development of novel drugs for human diseases.
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catalytic activities of mammalian epoxide hydrolases with cis and trans fatty acid Epoxides relevant to skin barrier function
Journal of Lipid Research, 2018Co-Authors: Bruce D. Hammock, Christophe Morisseau, Haruto Yamanashi, William E Boeglin, Robert W Davis, Gary A Sulikowski, Alan R BrashAbstract:Lipoxygenase (LOX)-catalyzed oxidation of the essential fatty acid, linoleate, represents a vital step in construction of the mammalian epidermal permeability barrier. Analysis of epidermal lipids indicates that linoleate is converted to a trihydroxy derivative by hydrolysis of an epoxy-hydroxy precursor. We evaluated different epoxide hydrolase (EH) enzymes in the hydrolysis of skin-relevant fatty acid Epoxides and compared the products to those of acid-catalyzed hydrolysis. In the absence of enzyme, exposure to pH 5 or pH 6 at 37°C for 30 min hydrolyzed fatty acid allylic epoxyalcohols to four trihydroxy products. By contrast, human soluble EH [sEH (EPHX2)] and human or murine epoxide hydrolase-3 [EH3 (EPHX3)] hydrolyzed cis or trans allylic Epoxides to single diastereomers, identical to the major isomers detected in epidermis. Microsomal EH [mEH (EPHX1)] was inactive with these substrates. At low substrate concentrations (
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probing the orientation of inhibitor and epoxy eicosatrienoic acid binding in the active site of soluble epoxide hydrolase
Archives of Biochemistry and Biophysics, 2017Co-Authors: Niel M Henriksen, Christophe Morisseau, Connie J Ng, Jun Yang, Armann Andaya, Michael K Gilson, Bruce D. HammockAbstract:Soluble epoxide hydrolase (sEH) is an important therapeutic target of many diseases, such as chronic obstructive pulmonary disease (COPD) and diabetic neuropathic pain. It acts by hydrolyzing and thus regulating specific bioactive long chain polyunsaturated fatty acid Epoxides (lcPUFA), like epoxyeicosatrienoic acids (EETs). To better predict which Epoxides could be hydrolyzed by sEH, one needs to dissect the important factors and structural requirements that govern the binding of the substrates to sEH. This knowledge allows further exploration of the physiological role played by sEH. Unfortunately, a crystal structure of sEH with a substrate bound has not yet been reported. In this report, new photoaffinity mimics of a sEH inhibitor and EET regioisomers were prepared and used in combination with peptide sequencing and computational modeling, to identify the binding orientation of different regioisomers and enantiomers of EETs into the catalytic cavity of sEH. Results indicate that the stereochemistry of the epoxide plays a crucial role in dictating the binding orientation of the substrate.
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oral treatment of rodents with soluble epoxide hydrolase inhibitor 1 1 propanoylpiperidin 4 yl 3 4 trifluoromethoxy phenyl urea tppu resulting drug levels and modulation of oxylipin pattern
Prostaglandins & Other Lipid Mediators, 2015Co-Authors: Annika I Ostermann, Bruce D. Hammock, Christophe Morisseau, Jan Herbers, Ina Willenberg, Rongjun Chen, Sung Hee Hwang, Robert Greite, Faikah Gueler, Nils Helge SchebbAbstract:Epoxides from polyunsaturated fatty acids (PUFAs) are potent lipid mediators. In vivo stabilization of these Epoxides by blockade of the soluble epoxide hydrolase (sEH) leads to anti-inflammatory, analgesic and normotensive effects. Therefore, sEH inhibitors (sEHi) are a promising new class of drugs. Herein, we characterized pharmacokinetic (PK) and pharmacodynamic properties of a commercially available potent sEHi 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU). Cell culture studies suggest its high absorption and metabolic stability. Following administration in drinking water to rats (0.2, 1, and 5mg TPPU/L with 0.2% PEG400), TPPU's blood concentration increased dose dependently within the treatment period to reach an almost steady state after 8 days. TPPU was found in all the tissues tested. The linoleic epoxide/diol ratios in most tissues were dose dependently increased, indicating significant sEH inhibition. Overall, administration of TPPU with the drinking water led to systemic distribution as well as high drug levels and thus makes chronic sEH inhibition studies possible.
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anti inflammatory effects of ω 3 polyunsaturated fatty acids and soluble epoxide hydrolase inhibitors in angiotensin ii dependent hypertension
Journal of Cardiovascular Pharmacology, 2013Co-Authors: Arzu Ulu, Christophe Morisseau, Todd R Harris, Christina Miyabe, Hiromi Inoue, Gertrud Schuster, Hua Dong, Anamaria Iosif, Junyan Liu, Robert H WeissAbstract:The mechanisms underlying the anti-inflammatory and anti-hypertensive effects of long chain ω-3 polyunsaturated fatty acids (PUFAs) are still unclear. The Epoxides of an ω-6 fatty acid, arachidonic acid (epoxyeicosatrienoic acids; EETs) also exhibit anti-hypertensive and anti-inflammatory effects. Thus, we hypothesized that the major ω-3 PUFAs including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may lower blood pressure and attenuate renal markers of inflammation through their epoxide metabolites. Here, we supplemented mice with an ω-3 rich diet for three weeks in a murine model of angiotensin-II dependent hypertension. Also, since EPA and DHA Epoxides are metabolized by soluble epoxide hydrolase (sEH), we tested the combination of a sEH inhibitor and the ω-3 rich diet. Our results show that ω-3 rich diet in combination with the sEH inhibitor lowered Ang-II increased blood pressure, further increased renal levels of EPA and DHA Epoxides, reduced renal markers of inflammation (i.e. prostaglandins and MCP-1), down-regulated an epithelial sodium channel and up-regulated Angiotensin converting enzyme-2 message (ACE-2) and significantly modulated cyclooxygenase and lipoxygenase metabolic pathways. Overall, our findings suggest that Epoxides of the ω-3 PUFAs contribute to lowering SBP and attenuating inflammation in part by reduced prostaglandins and MCP-1 and by up-regulation of ACE-2 in angiotensin-II dependent hypertension.
Karl J. Bonney - One of the best experts on this subject based on the ideXlab platform.
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A unifying stereochemical analysis for the formation of halogenated C15-acetogenin medium-ring ethers from Laurencia species via intramolecular bromonium ion assisted epoxide ring-opening and experimental corroboration with a model epoxide.
The Journal of organic chemistry, 2012Co-Authors: Karl J. Bonney, D. Christopher BraddockAbstract:A unifying stereochemical analysis for the formation of the constitutional isomeric halogenated C15-acetogenin medium-ring ether natural products from Laurencia species is presented, where an intramolecular bromonium ion assisted epoxide ring-opening reaction of enantiomerically pure Epoxides can account for ring-size, the position of the halogen substituents, and relative and absolute configurations of the known natural products. Experimentally, a model epoxide corroborates the feasibility of this process for concurrent formation of 7-, 8- and 9-ring ethers corresponding to the halogenated medium-ring ethers of known metabolites from Laurencia species.
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A Unifying Stereochemical Analysis for the Formation of Halogenated C15-Acetogenin Medium-Ring Ethers From Laurencia Species via Intramolecular Bromonium Ion Assisted Epoxide Ring-Opening and Experimental Corroboration with a Model Epoxide
2012Co-Authors: Karl J. Bonney, Christopher D. BraddockAbstract:A unifying stereochemical analysis for the formation of the constitutional isomeric halogenated C15-acetogenin medium-ring ether natural products from Laurencia species is presented, where an intramolecular bromonium ion assisted epoxide ring-opening reaction of enantiomerically pure Epoxides can account for ring-size, the position of the halogen substituents, and relative and absolute configurations of the known natural products. Experimentally, a model epoxide corroborates the feasibility of this process for concurrent formation of 7-, 8- and 9-ring ethers corresponding to the halogenated medium-ring ethers of known metabolites from Laurencia species
Bruce D. Hammock - One of the best experts on this subject based on the ideXlab platform.
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substrate and inhibitor selectivity and biological activity of an epoxide hydrolase from trichoderma reesei
Molecular Biology Reports, 2019Co-Authors: Gabriel S De Oliveira, Bruce D. Hammock, Christophe Morisseau, P P Adriani, Felipe S ChambergoAbstract:Epoxide hydrolases (EHs) are present in all living organisms and catalyze the hydrolysis of Epoxides to the corresponding vicinal diols. EH are involved in the metabolism of endogenous and exogenous Epoxides, and thus have application in pharmacology and biotechnology. In this work, we describe the substrates and inhibitors selectivity of an epoxide hydrolase recently cloned from the filamentous fungus Trichoderma reesei QM9414 (TrEH). We also studied the TrEH urea-based inhibitors effects in the fungal growth. TrEH showed high activity on radioative and fluorescent surrogate and natural substrates, especially Epoxides from docosahexaenoic acid. Using a fluorescent surrogate substrate, potent inhibitors of TrEH were identified. Interestingly, one of the best compounds inhibit up to 60% of T. reesei growth, indicating an endogenous role for TrEH. These data make TrEH very attractive for future studies about fungal metabolism of fatty acids and possible development of novel drugs for human diseases.
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catalytic activities of mammalian epoxide hydrolases with cis and trans fatty acid Epoxides relevant to skin barrier function
Journal of Lipid Research, 2018Co-Authors: Bruce D. Hammock, Christophe Morisseau, Haruto Yamanashi, William E Boeglin, Robert W Davis, Gary A Sulikowski, Alan R BrashAbstract:Lipoxygenase (LOX)-catalyzed oxidation of the essential fatty acid, linoleate, represents a vital step in construction of the mammalian epidermal permeability barrier. Analysis of epidermal lipids indicates that linoleate is converted to a trihydroxy derivative by hydrolysis of an epoxy-hydroxy precursor. We evaluated different epoxide hydrolase (EH) enzymes in the hydrolysis of skin-relevant fatty acid Epoxides and compared the products to those of acid-catalyzed hydrolysis. In the absence of enzyme, exposure to pH 5 or pH 6 at 37°C for 30 min hydrolyzed fatty acid allylic epoxyalcohols to four trihydroxy products. By contrast, human soluble EH [sEH (EPHX2)] and human or murine epoxide hydrolase-3 [EH3 (EPHX3)] hydrolyzed cis or trans allylic Epoxides to single diastereomers, identical to the major isomers detected in epidermis. Microsomal EH [mEH (EPHX1)] was inactive with these substrates. At low substrate concentrations (
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probing the orientation of inhibitor and epoxy eicosatrienoic acid binding in the active site of soluble epoxide hydrolase
Archives of Biochemistry and Biophysics, 2017Co-Authors: Niel M Henriksen, Christophe Morisseau, Connie J Ng, Jun Yang, Armann Andaya, Michael K Gilson, Bruce D. HammockAbstract:Soluble epoxide hydrolase (sEH) is an important therapeutic target of many diseases, such as chronic obstructive pulmonary disease (COPD) and diabetic neuropathic pain. It acts by hydrolyzing and thus regulating specific bioactive long chain polyunsaturated fatty acid Epoxides (lcPUFA), like epoxyeicosatrienoic acids (EETs). To better predict which Epoxides could be hydrolyzed by sEH, one needs to dissect the important factors and structural requirements that govern the binding of the substrates to sEH. This knowledge allows further exploration of the physiological role played by sEH. Unfortunately, a crystal structure of sEH with a substrate bound has not yet been reported. In this report, new photoaffinity mimics of a sEH inhibitor and EET regioisomers were prepared and used in combination with peptide sequencing and computational modeling, to identify the binding orientation of different regioisomers and enantiomers of EETs into the catalytic cavity of sEH. Results indicate that the stereochemistry of the epoxide plays a crucial role in dictating the binding orientation of the substrate.
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oral treatment of rodents with soluble epoxide hydrolase inhibitor 1 1 propanoylpiperidin 4 yl 3 4 trifluoromethoxy phenyl urea tppu resulting drug levels and modulation of oxylipin pattern
Prostaglandins & Other Lipid Mediators, 2015Co-Authors: Annika I Ostermann, Bruce D. Hammock, Christophe Morisseau, Jan Herbers, Ina Willenberg, Rongjun Chen, Sung Hee Hwang, Robert Greite, Faikah Gueler, Nils Helge SchebbAbstract:Epoxides from polyunsaturated fatty acids (PUFAs) are potent lipid mediators. In vivo stabilization of these Epoxides by blockade of the soluble epoxide hydrolase (sEH) leads to anti-inflammatory, analgesic and normotensive effects. Therefore, sEH inhibitors (sEHi) are a promising new class of drugs. Herein, we characterized pharmacokinetic (PK) and pharmacodynamic properties of a commercially available potent sEHi 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU). Cell culture studies suggest its high absorption and metabolic stability. Following administration in drinking water to rats (0.2, 1, and 5mg TPPU/L with 0.2% PEG400), TPPU's blood concentration increased dose dependently within the treatment period to reach an almost steady state after 8 days. TPPU was found in all the tissues tested. The linoleic epoxide/diol ratios in most tissues were dose dependently increased, indicating significant sEH inhibition. Overall, administration of TPPU with the drinking water led to systemic distribution as well as high drug levels and thus makes chronic sEH inhibition studies possible.
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eh3 abhd9 the first member of a new epoxide hydrolase family with high activity for fatty acid Epoxides
Journal of Lipid Research, 2012Co-Authors: Martina Decker, Bruce D. Hammock, Annette Cronin, Magdalena Adamska, Francesca Di Giallonardo, Julia Burgener, Anne Marowsky, John R Falck, Christophe Morisseau, Artiom GruzdevAbstract:Epoxide hydrolases are a small superfamily of enzymes important for the detoxification of chemically reactive xenobiotic Epoxides and for the processing of endogenous Epoxides that act as signaling molecules. Here, we report the identification of two human epoxide hydrolases: EH3 and EH4. They share 45% sequence identity, thus representing a new family of mammalian epoxide hydrolases. Quantitative RT-PCR from mouse tissue indicates strongest EH3 expression in lung, skin, and upper gastrointestinal tract. The recombinant enzyme shows a high turnover number with 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid (EET), as well as 9,10-epoxyoctadec-11-enoic acid (leukotoxin). It is inhibited by a subclass of N,N’-disubstituted urea derivatives, including 12-(3-adamantan-1-yl-ureido)-dodecanoic acid, 1-cyclohexyl-3-dodecylurea, and 1-(1-acetylpiperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea, compounds so far believed to be selective inhibitors of mammalian soluble epoxide hydrolase (sEH). Its sensitivity to this subset of sEH inhibitors may have implications on the pharmacologic profile of these compounds. This is particularly relevant because sEH is a potential drug target, and clinical trials are under way exploring the value of sEH inhibitors in the treatment of hypertension and diabetes type II.
Geoffrey W Coates - One of the best experts on this subject based on the ideXlab platform.
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Regioselective Carbonylation of 2,2-Disubstituted Epoxides: An Alternative Route to Ketone-Based Aldol Products
2019Co-Authors: Aran K. Hubbell, Anne M. Lapointe, Jessica R. Lamb, Geoffrey W CoatesAbstract:We report the regioselective carbonylation of 2,2-disubstituted Epoxides to β,β-disubstituted β-lactones. Mechanistic studies revealed epoxide ring-opening as the turnover limiting step, an insight that facilitated the development of improved reaction conditions using weakly donating, ethereal solvents. A wide range of Epoxides can be carbonylated to β-lactones, which are subsequently ring-opened to produce ketone-based aldol adducts, providing an alternative to the Mukaiyama aldol reaction. Enantiopure Epoxides were demonstrated to undergo the carbonylation/ring-opening process with retention of stereochemistry to form enantiopure β-hydroxy esters
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development of highly active and regioselective catalysts for the copolymerization of Epoxides with cyclic anhydrides an unanticipated effect of electronic variation
Journal of the American Chemical Society, 2016Co-Authors: Angela M Diciccio, Julie M Longo, Gabriel G Rodriguezcalero, Geoffrey W CoatesAbstract:Recent developments in polyester synthesis have established several systems based on zinc, chromium, cobalt, and aluminum catalysts for the ring-opening alternating copolymerization of Epoxides with cyclic anhydrides. However, to date, regioselective processes for this copolymerization have remained relatively unexplored. Herein we report the development of a highly active, regioselective system for the copolymerization of a variety of terminal Epoxides and cyclic anhydrides. Unexpectedly, electron withdrawing substituents on the salen framework resulted in a more redox stable Co(III) species and longer catalyst lifetime. Using enantiopure propylene oxide, we synthesized semicrystalline polyesters via the copolymerization of a range of epoxide/anhydride monomer pairs.
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enantioselective polymerization of Epoxides a highly active and selective catalyst for the preparation of stereoregular polyethers and enantiopure Epoxides
Journal of the American Chemical Society, 2008Co-Authors: Wataru Hirahata, Emil B Lobkovsky, Renee M Thomas, Geoffrey W CoatesAbstract:A chiral, bimetallic cobalt catalyst was discovered that is highly active and enantioselective for epoxide polymerization. The enantiomerically pure catalyst system exhibits a stereoselectivity factor (s = kfast/kslow) of 370 for propylene oxide, allowing enantiomerically pure epoxide to be recovered in nearly the maximum theoretical yield. In addition, the racemic catalyst forms highly isotactic poly(propylene oxide) in quantitative yield. The catalyst is active and selective for other Epoxides, such as 1-butene oxide, 1-hexene oxide, and styrene oxide.
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catalytic double carbonylation of Epoxides to succinic anhydrides catalyst discovery reaction scope and mechanism
Journal of the American Chemical Society, 2007Co-Authors: John M. Rowley, Emil B Lobkovsky, Geoffrey W CoatesAbstract:The first catalytic method for the efficient conversion of Epoxides to succinic anhydrides via one-pot double carbonylation is reported. This reaction occurs in two stages: first, the epoxide is carbonylated to a β-lactone, and then the β-lactone is subsequently carbonylated to a succinic anhydride. This reaction is made possible by the bimetallic catalyst [(ClTPP)Al(THF)2]+[Co(CO)4]- (1; ClTPP = meso-tetra(4-chlorophenyl)porphyrinato; THF = tetrahydrofuran), which is highly active and selective for both epoxide and lactone carbonylation, and by the identification of a solvent that facilitates both stages. The catalysis is compatible with substituted Epoxides having aliphatic, aromatic, alkene, ether, ester, alcohol, nitrile, and amide functional groups. Disubstituted and enantiomerically pure anhydrides are synthesized from Epoxides with excellent retention of stereochemical purity. The mechanism of epoxide double carbonylation with 1 was investigated by in situ IR spectroscopy, which reveals that the t...
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chromium iii octaethylporphyrinato tetracarbonylcobaltate a highly active selective and versatile catalyst for epoxide carbonylation
Journal of the American Chemical Society, 2005Co-Authors: Joseph A R Schmidt, Emil B Lobkovsky, Geoffrey W CoatesAbstract:The development of a highly active and selective porphyrin-based epoxide carbonylation catalyst, [(OEP)Cr(THF)2][Co(CO)4] (1; OEP = octaethylporphyrinato; THF = tetrahydrofuran), is detailed. Complex 1 is a separated ion pair composed of a tetracarbonylcobaltate anion and an octahedral chromium porphyrin complex axially ligated by two THF ligands. Regarding the carbonylation of Epoxides to β-lactones, catalyst 1 exhibits excellent turnover numbers (up to 10 000) and turnover frequencies (up to 1670 h-1), with regioselective carbonyl insertion occurring between the oxygen and the sterically less hindered carbon of the epoxide substrate. Complex 1 is highly tolerant of nonprotic functional groups, carbonylating an array of aliphatic and cycloaliphatic Epoxides, as well as Epoxides with pendant ethers, esters, and amides. With careful control of reaction conditions in the carbonylation of glycidyl esters, the exclusive production of either the β- or γ-lactone isomer was achieved. Through analysis of reaction...
