- Synthesis of 5-(S)-HETE, 5-(S)-HEPE and (+)-zooxanthellactone: Three hydroxylated polyunsaturated fatty acid metabolites
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Short and stereoselective syntheses of the two hydroxylated polyunsaturated fatty acid metabolites, namely 5-(S)-HETE and 5-(S)-HEPE, are reported in 23% and 30% overall yields, respectively. In addition, synthesis of the polyunsaturated fatty acid natura
- Primdahl, Karoline Gangestad,Stenstr?m, Yngve,Hansen, Trond Vidar,Vik, Anders
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- Synthesis, molecular modelling studies and biological evaluation of new oxoeicosanoid receptor 1 agonists
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The oxoeicosanoid receptor 1 (OXER1) is a member of the G-protein coupled receptors (GPCR) family, and is involved in inflammatory processes and oncogenesis. As such it is an attractive target for pharmacological intervention. The present study aimed to shed light on the molecular fundaments of OXER1 modulation using chemical probes structurally related to the natural agonist 5-oxo-ETE. In a first step, 5-oxo-ETE and its closely related derivatives (5-oxo-EPE and 4-oxo-DHA) were obtained by conducting concise and high-yielding syntheses. The biological activity of obtained compounds was assessed in terms of potency (EC50) and efficacy (Emax) for arrestin recruitment. Finally, molecular modelling and simulation were used to explore binding characteristics of 5-oxo-ETE and derivatives with the aim to rationalize biological activity. Our data suggest that the tested 5-oxo-ETE derivatives (i) insert quickly into the membrane, (ii) access the receptor via transmembrane helices (TMs) 5 and 6 from the membrane side and (iii) drive potency and efficacy by differential interaction with TM5 and 7. Most importantly, we found that the methyl ester of 5-oxo-ETE (1a) showed even a higher maximum response than the natural agonist (1). In contrast, shifting the 5-oxo group into position 4 results in inactive compounds (4-oxo DHA compounds (3) and (3a)). All in all, our study provides relevant structural data that help understanding better OXER1 functionality and its modulation. The structural information presented herein will be useful for designing new lead compounds with desired signalling profiles.
- Stepniewski, Tomasz Maciej,Torrens-Fontanals, Mariona,Rodríguez-Espigares, Ismael,Giorgino, Toni,Primdahl, Karoline G.,Vik, Anders,Stenstr?m, Yngve,Selent, Jana,Hansen, Trond Vidar
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p. 3580 - 3587
(2018/06/06)
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- Identification and absolute configuration of dihydroxy-arachidonic acids formed by oxygenation of 5 S-HETE by native and aspirin-acetylated COX-2
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Biosynthesis of the prostaglandin endoperoxide by the cyclooxygenase (COX) enzymes is accompanied by formation of a small amount of 11 R- hydroxyeicosatetraenoic acid (HETE), 15 R-HETE, and 15 S-HETE as by-products. Acetylation of COX-2 by aspirin abrogates prostaglandin synthesis and triggers formation of 15 R-HETE as the sole product of oxygenation of arachidonic acid. Here, we investigated the formation of by-products of the transformation of 5 S-HETE by native COX-2 and by aspirin-acetylated COX-2 using HPLC-ultraviolet, GC-MS, and LC-MS analysis. 5 S,15 S-dihydroxy (di)HETE, 5 S,15 R-diHETE, and 5 S,11 R-diHETE were identified as by-products of native COX-2, in addition to the previously described di-endoperoxide (5 S,15 S-dihydroxy-9 S,11 R,8 S,12 S-diperoxy-6 E,13 E-eicosadienoic acid) as the major oxygenation product. 5 S,15 R-diHETE was the only product formed by aspirinacetylated COX-2. Both 5,15-diHETE and 5,11-diHETE were detected in CT26 mouse colon carcinoma cells as well as in lipopolysaccharide-activated RAW264.7 cells incubated with 5 S-HETE, and their formation was attenuated in the presence of the COX-2 specific inhibitor, NS-398. Aspirintreated CT26 cells gave 5,15-diHETE as the most prominent product formed from 5 S-HETE. 5 S,15 S-diHETE has been described as a product of the cross-over of 5-lipoxygenase (5-LOX) and 15-LOX activities in elicited rat mononuclear cells and human leukocytes, and our studies implicate crossover of the 5-LOX and COX-2 pathways as an additional biosynthetic route. Copyright
- Mulugeta, Surafel,Suzuki, Takashi,Hernandez, Noemi Tejera,Griesser, Markus,Boeglin, William E.,Schneider, Claus
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experimental part
p. 575 - 585
(2010/09/04)
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- Reductive deprotection of silyl groups with Wilkinson's catalyst/catechol borane
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Traditionally silyl groups are deprotected with acids and fluorides. These methods are, however, less discriminating when multi-silyl groups are present in the same molecule, resulting in lower yields of the desired products. The manipulation of these functions during the total synthesis of natural products, for example, prostaglandins and isoprostanes, requires the selective protection and deprotection of these groups. We are reporting here on a mild, selective and efficient method for the reductive deprotection of silyl groups using Wilkinson's catalyst/catechol borane or catechol borane alone.
- Patel, Pranav,Chang, Chih-Tsung,Kang, Namin,Lee, Gue-Jae,Powell, William S.,Rokach, Joshua
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p. 5289 - 5292
(2008/02/09)
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- Synthesis of polyconjugated fatty acids
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The present invention relates to fatty acids. In particular, the present invention provides polyconjugated fatty acids, and methods of their synthesis and their use.
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- Synthesis of long chain n-3 and n-6 fatty acids having a photoactive conjugated tetraene group
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Fatty acids of the n-3 and n-6 families containing a photoactive conjugated tetraene group near the carboxylate were prepared from several naturally occurring fatty acids by sequential iodolactonization and treatment with excess 1,8-diazabicyclo[5.4.0]undec-7-ene. The new conjugated fatty acids include 5E,7E,9E,11Z,14Z- and 5E,7E,9E,11E,14Z-eicosapentaenoic acids derived from arachidonic acid; 5E,7E,9E,11Z,14Z,17Z- and 5E,7E,9E,11E,14Z,17Z-eicosahexaenoic acids from eicosapentaenoic acid; and 4E,6E,8E,10Z,13Z,16Z,19Z- and 4E,6E,8E,10E,13Z,16Z,19Z-docosaheptaenoic acids from docosahexaenoic acid. All of the newly synthesized fatty acids were characterized by UV, 1H NMR and mass spectroscopy. These new products represent the first examples of directed conjugation of methylene interrupted double bond systems. The products can be synthesized in gram quantities and in high yields (>50%). Interestingly, it did not prove possible to synthesize fatty acids having a triene group near the carboxyl group even using mild conditions and different synthetic approaches. Once initiated, the isomerization always continued until a tetraene group was formed. Because of the sensitivity of the tetraene group to light, these fatty acids have the potential for being used in tracking fatty acid movements in cells employing fluorescence techniques and in UV light-induced cross linking to membrane proteins.
- Kuklev, Dmitry V.,Smith, William L.
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p. 145 - 158
(2007/10/03)
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- 5-HETE congeners as modulators of cell proliferation
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The synthesis and assessment of the mitogenic properties of 5-HETE congeners are reported. These studies represent an effort to develop a structure-activity profile for ligands of the 5-HETE/5-oxoETE G-protein coupled receptor(s). Many of these agents possess mitogenic activity that equals or exceeds that of racemic 5-HETE family constituents in prostate cancer cell lines. (C) 2000 Elsevier Science Ltd.
- Miller, Thomas A.,Ghosh, Jagadananda,Myers, Charles E.,Macdonald, Timothy L.
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p. 1913 - 1916
(2007/10/03)
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- An efficient total synthesis of 5-(S)-HETE
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A short and convergent synthesis of (5S)-HETE 1a was accomplished by coupling of two easily accessible synthons 2 and 3a.
- Gueugnot, Sylvie,Alami, Mouad,Linstrumelle, Gerard,Mambu, Lengo,Petit, Yves,Larcheveque, Marc
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p. 6635 - 6646
(2007/10/03)
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- A chemoenzymatic approach to hydroperoxyeicosatetraenoic acids. Total synthesis of 5(S)-HPETE
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A new synthetic approach to enantiomerically pure hydroperoxyeicosatetraenoic acids (HPETEs) is described in which the tetraene skeleton is assembled through chemoselective olefination of a protected hydroperoxy aldehyde. Soybean lipoxygenase-mediated dioxygenation of both natural and unnatural fats produces hydroperoxy dienes in high enantiomeric excess; the observed regioselectivity supports a revised hypothesis for substrate specificity. Protection of the diene hydroperoxides as peroxy ketals is followed by regioselective ozonolysis to afford enantiomerically pure 4-peroxy 2,3-enals which undergo olefination to produce peroxytetraenoates. Removal of the monoperoxy ketal and the methyl ester affords enantiomerically pure HPETEs. The generality of the strategy is illustrated with the first chemical synthesis of 5(S)-HPETE.
- Dussault,Lee
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p. 218 - 226
(2007/10/02)
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- Stereochemistry and Mechanism of the Biosynthesis of Leukotriene A4 from 5(S)-Hydroperoxy-6(E),8,11,14(Z)-eicosatetraenoic Acid. Evidence for an Organoiron Intermediate
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The pathway of biosynthesis of leukotriene A4 (LTA4, 2) from 5(S)-hydroperoxy-6(E),8,11,14(Z)-eicosatetraenoic acid (5-S-HPETE, 1) has been explored by the comparative study of (S)- and (R)-lipoxygenase (LO) enzymes as catalysts.The purified LO from potato, an S-lipoxygenase, converts (anaerobically) 1 to 2 (determined as the characteristic hydrolysis mixture of two epimeric 5,6-diols and two epimeric 5,12-diols), as previously reported by Samuelsson et al.However, the 8-R-LO from the coral Plexaura homomalla transforms 1 (anaerobically) into 6-epi-LTA4 (6).Theobserved divergence of stereopathways agrees with predictions based on the intermediacy of organoiron intermediates in enzymic lipoxygenation (Scheme I) and detailed in Schemes II and III.Further evidence for the intervention of such intermediates has been obtained by trapping experiments under pure O2 at pressures of 1-60 atm.Under O2 pressure 1 is converted by the potato LO to a new product, the bis(hydroperoxide) 7, whereas the coral LO converts 1 to the diastereomeric bis(hydroperoxide) 9.
- Corey, E. J.,Wright, Stephen W.,Matsuda, Seiichi P. T.
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p. 1452 - 1455
(2007/10/02)
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- A General Strategy for the Synthesis of Monohydroxyeicosatetraenoic Acids: Total Synthesis of 5(S)-Hydroxy-6(E),8,11,14(Z)-eicosatetraenoic Acid (5-HETE) and 12(S)-Hydroxy-5,8,14(Z),10(E)-eicosatetraenoic Acid (12-HETE)
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Stereocontrolled total syntheses of 5(S)-hydroxy-6(E),8,11,14(Z)-eicosatetraenoic acid (5-HETE) and 12(S)-hydroxy-5,8,14(Z),10(E)-eicosatetraenoic acid (12-HETE) via palladium(0)-copper(I) coupling technology are described.
- Nicolaou, K. C.,Ladduwahetty, T.,Taffer, I. M.,Zipkin, R. E.
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p. 344 - 347
(2007/10/02)
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- Absolute Configuration of Epoxyeicosatrienoic Acids (EETs) Formed during Catalytic Oxygenation of Arachidonic Acid by Purified Rat Liver Microsomal Cytochrome P-450
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Incubation of arachidonic acid with a reconstituted enzymatic system containing a purified preparation of the major, phenobarbital-inducible form of rat liver microsomal cytochrome P-450, NADPH, cytochrome b5, and NADPH-cytochrome P-450 reductase affords as the principal products four regioisomeric cis-epoxides: 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs).Their absolute configurations were established by conversion to the corresponding hydroxyeicosatetraenoic acid (HETE) methyl esters, derivatization with dehydroabiethylisocyanate, and chromatographic analysis.Except for 5,6-EET, the cytochrome P-450 catalyzed epoxidation is highly enantioselective.
- Falck, J. R.,Manna, S.,Jacobson, Harry R.,Estabrook, R. W.,Chacos, N.,Capdevila, Jorge
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p. 3334 - 3336
(2007/10/02)
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- A new general method for the synthesis of lipoxygenase products: Preparation of ±5-HETE
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Recognizing 3 as the basic common unit in the structures of all HETEs, a general synthetic approach is proposed. As an illustration of this method, the synthesis of ±5-HETE was accomplished using the marked diene 8.
- Rokach,Adams,Perry
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p. 5185 - 5188
(2007/10/02)
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- FORMATION AND STRUCTURE DETERMINATION OF 5,6-EPOXY-8,11,14-Z-EICOSATRIENOIC ACID AND 5-OXO-8,11,14-Z-EICOSATRIENOIC ACID
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The formation of 5,6-epoxy-8,11,14-Z-eicosatrienoic acid and 5-oxo-8,11,14-Z-eicosatrienoic acid as by-products in the synthesis of 5-hydroxy-6-E-8,11,14-Z-eicosatetraenoic acid is described.
- Spur, Bernd,Crea, Attilio,Peters, Wilfried
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p. 1755 - 1758
(2007/10/02)
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- A PRACTICAL PROCESS FOR LARGE-SCALE SYNTHESIS OF (S)-5-HYDROXY-6-TRANS-8,11,14-CIS-EICOSATETRAENOIC ACID (5-HETE)
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(S)-5-hydroxy-6-trans-8,11,14-cis-eicosatetraenoic acid (5-HETE) (1) and its enantiomer are readily available by a chemical synthesis from arachidonic acid which includes a chromatographic separation of diastereomeric urethanes (3) made from (+/-)-5-HETE methyl ester and the isocyanate 4 derived from dehydroabietylamine.
- Corey, E. J.,Hashimoto, Shun-ichi
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p. 299 - 302
(2007/10/02)
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