- Electrophilic fatty acid nitroalkenes are systemically transported and distributed upon esterification to complex lipids
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Electrophilic nitro-fatty acids [NO2-FAs (fatty acid nitroalkenes)] showed beneficial signaling actions in preclinical studies and safety in phase 1 clinical trials. A detailed description of the pharmacokinetics (PK) of NO2-FAs is complicated by the capability of electrophilic fatty acids to alkylate thiols reversibly and become esterified in various complex lipids, and the instability of the nitroalkene moiety during enzymatic and base hydrolysis. Herein, we report the mechanism and kinetics of absorption, metabolism, and distribution of the endogenously detectable and prototypical NO2-FA, 10-nitro-oleic acid (10-NO2-OA), in dogs after oral administration. Supported by HPLC-high-resolution-MS/MS analysis of synthetic and plasma-derived 10-NO2-OA-containing triacylglycerides (TAGs), we show that a key mechanism of NO2-FA distribution is an initial esterification into complex lipids. Quantitative analysis of plasma free and esterified lipid fractions confirmed time-dependent preferential incorporation of 10-NO2-OA into TAGs when compared with its principal metabolite, 10-nitro-stearic acid. Finally, new isomers of 10-NO2-OA were identified in vivo, and their electrophilic reactivity and metabolism characterized. Overall, we reveal that NO2-FAs display unique PK, with the principal mechanism of tissue distribution involving complex lipid esterification, which serves to shield the electrophilic character of this mediator from plasma and hepatic inactivation and thus permits efficient distribution to target organs.—Fazzari, M., D. A. Vitturi, S. R. Woodcock, S. R. Salvatore, B. A. Freeman, and F. J. Schopfer. Electrophilic fatty acid nitroalkenes are systemically transported and distributed upon esterification to complex lipids.
- Fazzari, Marco,Vitturi, Dario A.,Woodcock, Steven R.,Salvatore, Sonia R.,Freeman, Bruce A.,Schopfer, Francisco J.
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- Synthesis of 1-Palmitoyl-2-((E)-9- and (E)-10-nitrooleoyl)- sn -glycero-3-phosphatidylcholines
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Extensive investigation of nitrated phospholipids in connection with various biologically important processes requires reliable access to suitable material. A selective chemical synthesis introducing a defined nitrofatty acid at the sn -2 position of a 2-lyso sn -glycero-3-phosphatidylcholine was developed. Given that the nitroalkene moiety of both reactant nitrofatty acid derivative and the product esters is characterised by particular sensitivity to nucleophile addition and, depending on the intermediate, subsequent olefin isomerisation and retro-Henry-type reaction, a reliable two-step ester formation was introduced. The activation of the nitrofatty acid succeeded after reaction with trichlorobenzoyl chloride, and the mixed anhydride could be isolated via extractive work-up. Subsequent reaction with 1-palmitoyl-2-lyso- sn -glycero-3-phosphatidylcholine enabled the sn -2 esterification to be achieved with high yield by using a minimum of reagents, avoiding the formation of side products and facilitating final isolation and purification.
- Dietz, Ulrich,Frank, Andrea,Lehr, Alexander,Münch, Winfried,Nubbemeyer, Udo
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supporting information
p. 3295 - 3304
(2019/08/28)
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- The chemical basis of thiol addition to nitro-conjugated linoleic acid, a protective cell-signaling lipid
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Nitroalkene fatty acids are formed in vivo and exert protective and anti-inflammatory effects via reversible Michael addition to thiol-containing proteins in key signaling pathways. Nitro-conjugated linoleic acid (NO2-CLA) is preferentially formed, constitutes the most abundant nitrated fatty acid in humans, and contains two carbons that could potentially react with thiols, modulating signaling actions and levels. In this work, we examined the reactions of NO2-CLA with low molecular weight thiols (glutathione, cysteine, homocysteine, cysteinylglycine, and β-mercaptoethanol) and human serum albumin. Reactions followed reversible biphasic kinetics, consistent with the presence of two electrophilic centers in NO2-CLA located on the β- and δ-carbons with respect to the nitro group. The differential reactivity was confirmed by computational modeling of the electronic structure. The rates (kon and koff) and equilibrium constants for both reactions were determined for different thiols. LC-UV-Visible and LC-MS analyses showed that the fast reaction corresponds to β-adduct formation (the kinetic product), while the slow reaction corresponds to the formation of the δ-adduct (the thermodynamic product). The pH dependence of the rate constants, the correlation between intrinsic reactivity and thiol pKa, and the absence of deuterium solvent kinetic isotope effects suggested stepwise mechanisms with thiolate attack on NO2-CLA as rate-controlling step. Computational modeling supported the mechanism and revealed additional features of the transition states, anionic intermediates, and final neutral products. Importantly, the detection of cysteine-δ-adducts in human urine provided evidence for the biological relevance of this reaction. Finally, human serum albumin was found to bind NO2-CLA both non-covalently and to form covalent adducts at Cys-34, suggesting potential modes for systemic distribution. These results provide new insights into the chemical basis of NO2-CLA signaling actions.
- Turell, Lucía,Vitturi, Darío A.,Coiti?o, E. Laura,Lebrato, Lourdes,M?ller, Matías N.,Sagasti, Camila,Salvatore, Sonia R.,Woodcock, Steven R.,Alvarez, Beatriz,Schopfer, Francisco J.
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p. 1145 - 1159
(2017/07/11)
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- Modular Regiospecific Synthesis of Nitrated Fatty Acids
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Endogenous nitrated fatty acids are an important class of signaling molecules. Herein a modular route for the efficient and regiospecific preparation of nitrooleic acids as well as various analogues is described. The approach is based on a simple set of alkyl halides as common building blocks and a Henry reaction/Burgess dehydration sequence for the formation of the key nitroalkene moiety.
- Hock, Katharina J.,Grimmer, Jennifer,G?bel, Dominik,Gasaya, George Gichogo T.,Roos, Jessica,Maucher, Isabelle V.,Kühn, Benjamin,Fettel, Jasmin,Maier, Thorsten J.,Manolikakes, Georg
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p. 615 - 636
(2017/01/25)
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- BIOPASSIVATING MEMBRANE STABILIZATION BY MEANS OF NITROCARBOXYLIC ACID-CONTAINING PHOSPHOLIPIDS IN PREPARATIONS AND COATINGS
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The present invention relates to nitro-carboxylic acid (s)-containing phospholipids, to be used for coating of medical devices such as stents, catheter balloons, wound pads or surgical suture material and for bio-passivating compositions, such as rinses, waterproofing solutions, coating solutions, cryoprotection solutions, cold preservation media, lyoprotection solutions, contrast media solutions, preservation and reperfusion solutions containing these compounds as well as preparing solutions thereof and coating medical devices as well as their uses.
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Page/Page column
(2014/04/18)
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- Improved synthesis of (E)-12-nitrooctadec-12-enoic acid, a potent PPARγ activator. development of a "buffer-Free" enzymatic method for hydrolysis of methyl esters
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Endogenous nitro-fatty acids, acting as partial agonist of PPARγ, are able to lower the insulin and glucose levels without the side effects associated with common antidiabetic drugs. (E)-12-Nitrooctadec-12-enoic acid, a potent activator of this peroxisome receptor, was synthesized in a very efficient sequence via a Henry-retro-Claisen ring fragmentation, followed by a novel enzymatic cleavage of methyl esters. The latter method was then applied in the last step of the synthesis of a few labile natural products, such as prostaglandins, isoprostanes, and phytoprostanes.
- Zanoni, Giuseppe,Valli, Matteo,Bendjeddou, Lyamin,Porta, Alessio,Bruno, Paolo,Vidari, Giovanni
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supporting information; experimental part
p. 8311 - 8314
(2011/02/28)
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- Regio- and stereospecific syntheses and nitric oxide donor properties of (E)-9- and (E)-10-nitrooctadec-9-enoic acids
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Nitrated fatty acids act as endogenous peroxisome proliferator-activated receptor γ (PPARγ) ligands and nitric oxide (NO) donors. We describe the first specific preparation of the two regioisomers of nitrooleic acid, (E)-9-nitrooctadec-9-enoic acid (1) an
- Gorczynski, Michael J.,Huang, Jinming,King, S. Bruce
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p. 2305 - 2308
(2007/10/03)
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- Synthesis of nitrolipids. All four possible diastereomers of nitrooleic acids: (E)- and (Z)-, 9- and 10-nitro-octadec-9-enoic acids
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Unsaturated fatty acids are nitrated endogenously to produce nitrated lipids. Recent studies have shown that these nitrated lipids have high chemical reactivity and profound biological implications. We report an efficient, scalable synthesis which is regiospecific and stereoselective for all possible isomers of nitrated oleic acid: (E)- and (Z)-, 9- and 10-octadec-9-enoic acids.
- Woodcock, Steven R.,Marwitz, Adam J. V.,Bruno, Paulo,Branchaud, Bruce P.
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p. 3931 - 3934
(2007/10/03)
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- NITRATED LIPIDS AND METHODS OF MAKING AND USING THEREOF
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Described herein are nitrated lipids and methods of making and using the nitrated lipids.
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Page/Page column 40-41
(2008/06/13)
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