- 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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- Pharmacokinetics and Metabolism of Selective Oxoeicosanoid (OXE) Receptor Antagonists and Their Effects on 5-Oxo-6,8,11,14-eicosatetraenoic Acid (5-Oxo-ETE)-Induced Granulocyte Activation in Monkeys
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The potent eosinophil chemoattractant 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is a 5-lipoxygenase product that acts via the selective OXE receptor, which is present in many species, but not rodents. We previously reported that the indole 230 is
- Cossette, Chantal,Chourey, Shishir,Ye, Qiuji,Nagendra Reddy, Chintam,Gore, Vivek,Gravel, Sylvie,Slobodchikova, Irina,Vuckovic, Dajana,Rokach, Joshua,Powell, William S.
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p. 10127 - 10146
(2016/12/07)
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- Inhibitory and mechanistic investigations of oxo-lipids with human lipoxygenase isozymes
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Oxo-lipids, a large family of oxidized human lipoxygenase (hLOX) products, are of increasing interest to researchers due to their involvement in different inflammatory responses in the cell. Oxo-lipids are unique because they contain electrophilic sites that can potentially form covalent bonds through a Michael addition mechanism with nucleophilic residues in protein active sites and thus increase inhibitor potency. Due to the resemblance of oxo-lipids to LOX substrates, the inhibitor potency of 4 different oxo-lipids; 5-oxo-6,8,11,14-(E,Z,Z,Z)-eicosatetraenoic acid (5-oxo-ETE), 15-oxo-5,8,11,13-(Z,Z,Z,E)-eicosatetraenoic acid (15-oxo-ETE), 12-oxo-5,8,10,14-(Z,Z,E,Z)-eicosatetraenoic acid (12-oxo-ETE), and 13-oxo-9,11-(Z,E)-octadecadienoic acid (13-oxo-ODE) were determined against a library of LOX isozymes; leukocyte 5-lipoxygenase (h5-LOX), human reticulocyte 15-lipoxygenase-1 (h15-LOX-1), human platelet 12-lipoxygenase (h12-LOX), human epithelial 15-lipoxygenase-2 (h15-LOX-2), soybean 15-lipoxygenase-1 (s15-LOX-1), and rabbit reticulocyte 15-LOX (r15-LOX). 15-Oxo-ETE exhibited the highest potency against h12-LOX, with an IC50 = 1 ± 0.1 μM and was highly selective. Steady state inhibition kinetic experiments determined 15-oxo-ETE to be a mixed inhibitor against h12-LOX, with a Kic value of 0.087 ± 0.008 μM and a Kiu value of 2.10 ± 0.8 μM. Time-dependent studies demonstrated irreversible inhibition with 12-oxo-ETE and h15-LOX-1, however, the concentration of 12-oxo-ETE required (Ki = 36.8 ± 13.2 μM) and the time frame (k2 = 0.0019 ± 0.00032 s-1) were not biologically relevant. These data are the first observations that oxo-lipids can inhibit LOX isozymes and may be another mechanism in which LOX products regulate LOX activity.
- Armstrong, Michelle M.,Diaz, Giovanni,Kenyon, Victor,Holman, Theodore R.
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p. 4293 - 4297
(2014/08/18)
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- Biosynthesis, isolation, and NMR analysis of leukotriene A epoxides: Substrate chirality as a determinant of the cis or trans epoxide confi guration
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Leukotriene (LT)A 4 and closely related allylic epoxides are pivotal intermediates in lipoxygenase (LOX) pathways to bioactive lipid mediators that include the leukotrienes, lipoxins, eoxins, resolvins, and protectins. Although the structure and stereochemistry of the 5-LOX product LTA 4 is established through comparison to synthetic standards, this is the exception, and none of these highly unstable epoxides has been analyzed in detail from enzymatic synthesis. Understanding of the mechanistic basis of the cis or trans epoxide confi guration is also limited. To address these issues, we developed methods involving biphasic reaction conditions for the LOX-catalyzed synthesis of LTA epoxides in quantities suffi cient for NMR analysis. As proof of concept, human 15-LOX-1 was shown to convert 15 S-hydroperoxy-eicosatetraenoic acid (15 S-HPETE) to the LTA analog 14 S ,15 S-trans-epoxy-eicosa-5 Z ,8 Z ,10 E ,12 E-tetraenoate, confi rming the proposed structure of eoxin A 4 . Using this methodology we then showed that recombinant Arabidopsis AtLOX1, an arachidonate 5-LOX, converts 5 S-HPETE to the trans epoxide LTA 4 and converts 5 R-HPETE to the cis epoxide 5-epi-LTA 4 , establishing substrate chirality as a determinant of the cis or trans epoxide confi guration. The results are reconciled with a mechanism based on a dual role of the LOX nonheme iron in LTA epoxide biosynthesis, providing a rational basis for understanding the stereochemistry of LTA epoxide intermediates in LOX-catalyzed transformations.Copyright
- Jin, Jing,Zheng, Yuxiang,Boeglin, William E.,Brash, Alan R.
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p. 754 - 761
(2013/05/09)
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- METHOD OF SYNTHESIZING A 5-OXO-CONJUGATED FATTY ACID
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There is provided a novel chemical synthetic method for the preparation of a 5-oxo-ETE and related compounds. The method is based on a short and efficient synthesis of 5-oxo-ETE from commercially available Arachidonic acid. The method is based on the surprising discovery that a 5-oxo-conjugated fatty acid may be efficiently converted into the corresponding 5-oxo-conjugated fatty acid by reaction with the Dess-Martin reagent (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one)in the presence of pyridine or a substituted pyridine.
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Page/Page column 10
(2011/11/06)
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- Efficient total synthesis of 5-oxo-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic acid (5-oxo-ETE), a potent proinflammatory autacoid
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The title eicosanoid was prepared in good overall yield via a convergent aldol strategy that obviates the need for HPLC separation of olefinic isomers.
- Mohapatra, Suchismita,Capdevila, Jorge H.,Murphy, Robert C.,Hevko, John M.,Falck
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p. 4109 - 4110
(2007/10/03)
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- The Total Synthesis of Tritiated and Deuterated 5-Oxo-ETE, a Novel Inflammatory Mediator
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The total synthesis of 11,12,14,15-tetratritiated and deuterated 5-oxo-ETE is accomplished using a novel bisacetylene precursor 14. The syntheses of these labeled derivatives are necessary in order to investigate further the role and biochemistry of the novel inflammatory mediator and eosinophilic chemotactic agent 5-oxo-ETE.
- Khanapure, Subhash P.,Shi, Xiao-Xin,Powell, William S.,Rokach, Joshua
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p. 4098 - 4102
(2007/10/03)
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- Total Synthesis of a Potent Proinflammatory 5-Oxo-ETE and Its 6,7-Dihydro Biotransformation Product
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The first total synthesis of a potent inflammatory mediator 5-oxo-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic acid (5-oxo-ETE) 2 and its biotransformation product 6,7-dihydro-5-oxo-ETE 5 is reported. A convergent synthesis for the unstable title compounds is a
- Khanapure, Subhash P.,Shi, Xiao-Xin,Powell, William S.,Rokach, Joshua
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p. 337 - 342
(2007/10/03)
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