Total Synthesis of Iso[4]-levuglandin E<sub>2</sub>

Subbanagounder, Ganesamoorthy; Salomon, Robert G.; Murthi, Krishna K.; Brame, Cynthia J.; Roberts, L. Jackson

doi:10.1021/jo970858f

Cited by 32 publications

(35 citation statements)

References 25 publications

(38 reference statements)

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“…Base hydrolysis and acidification during extraction can alter or destroy the reactive allylic epoxide functionality present in these molecules. It is known that molecules containing allylic epoxide functionality can add nucleophiles such as methanol and amines (26,40) and undergo rearrangements (41). We observed addition of CD 3 OD to PEIPC when lipids were extracted with CHCl 3 /(CD 3 ) 3 OD under certain conditions (data not shown).…”

Section: Discussionmentioning

confidence: 72%

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Structural Identification of a Novel Pro-inflammatory Epoxyisoprostane Phospholipid in Mildly Oxidized Low Density Lipoprotein

Watson¹,

Subbanagounder²,

Welsbie³

et al. 1999

Journal of Biological Chemistry

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205

207

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One of the earliest steps in the development of the atherosclerotic lesion is the accumulation of monocyte/ macrophages within the vessel wall. Oxidized lipids present in minimally modified-low density lipoproteins (MM-LDL) contribute to this process by activating endothelial cells to express monocyte-specific adhesion molecules and chemoattractant factors. A major focus of our group has been the isolation and characterization of the biologically active oxidized lipids in MM-LDL. We have previously characterized three oxidized phospholipids present in MM-LDL, atherosclerotic lesions of fat fed rabbits, and autoxidized 1-palmitoyl-2-arachidonoyl-snglycero-3-phosphocholine (Ox-PAPC) that induced human aortic endothelial cells to adhere human monocytes in vitro. We have used sequential normal and reverse phase-high performance liquid chromatography to isolate various isomers of an oxidized phospholipid from autoxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine. The fatty acid in the sn-2 position of this biologically active isomer and its dehydration product was released by phospholipase A 2 and characterized. Hydrogenation with platinum(IV) oxide/hydrogen suggested a cyclic moiety, and reduction with sodium borohydride suggested two reducible oxygencontaining groups in the molecule. The fragmentation pattern produced by electrospray ionization-collision induced dissociation-tandem mass spectrometry was consistent with a molecule resembling an E-ring prostaglandin with an epoxide at the 5,6 position. The structure of this lipid was confirmed by proton nuclear magnetic resonance spectroscopy analysis of the free fatty acid isolated from the dehydration product of m/z 828.5. Based on these studies, we arrived at the structure of the biologically active oxidized phospholipids as 1-palmitoyl-2-(5,6-epoxyisoprostane E 2 )-sn-glycero-3-phosphocholine. The identification of this molecule adds epoxyisoprostanes to the growing list of biologically active isoprostanes.

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Section: Discussionmentioning

confidence: 72%

“…4). Previous studies have shown that both epoxide and carbonyl groups add amines (26,27). ESI-MS/MS analysis of the fatty acid isolated from m/z 810.5 (i2) (Fig.…”

Section: Discussionmentioning

confidence: 96%

Structural Identification of a Novel Pro-inflammatory Epoxyisoprostane Phospholipid in Mildly Oxidized Low Density Lipoprotein

Watson¹,

Subbanagounder²,

Welsbie³

et al. 1999

Journal of Biological Chemistry

Self Cite

205

207

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“…Sodium borohydride reduction and derivatization of oxidized phospholipids with methoxylamine hydrochloride and bis(trimethylsilyl)trifluoroacetamide (BSTFA) were performed as described previously (5,7,16). Selective epoxide hydrolysis of oxidized phospholipids was performed as described previously using PCA (1.66 mM) in HEPES buffer (17).…”

Section: Methodsmentioning

confidence: 99%

Epoxyisoprostane and Epoxycyclopentenone Phospholipids Regulate Monocyte Chemotactic Protein-1 and Interleukin-8 Synthesis

Subbanagounder¹,

Wong²,

Lee³

et al. 2002

Journal of Biological Chemistry

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173

177

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Monocyte recruitment to the vessel wall, mediated by monocyte chemotactic protein-1 (MCP-1) and interleukin-8 (IL-8), plays an important role in atherogenesis. We have shown previously that minimally oxidized low density lipoprotein, oxidized 1-palmitoyl-2-arachidonylsn-glycero-3-phosphorylcholine (Ox-PAPC), activates endothelial cells to produce MCP-1 and IL-8. By using liquid chromatography/mass spectrometry methods coupled with bioassay, we report a family of epoxyisoprostane (PEIPC) and epoxycyclopentenone (PECPC) phospholipids that are the components of Ox-PAPC responsible for the majority of this activity. Ox-PAPC contains five chromatographically distinguishable active PEIPC components (m/z 825.5) and four PECPC components (m/z 810.5). All nine components induced endothelial cell synthesis of IL-8 and MCP-1 in a dose-dependent fashion between 0.1 and 5 M concentrations. The five PEIPC components had identical functional groups and all underwent dehydration to produce m/z 810.5. We present evidence that these phospholipids are regioisomers with epoxide groups at the 5,6-, 8,9-, 11,12-, or 14,15-positions of the sn-2 fatty acid and their epoxide groups is important for biological activity. We have shown previously that peroxisome proliferator-activated receptor ␣ is involved in MCP-1 synthesis in response to Ox-PAPC. We now show that PEIPC and PECPC isomers are potent activators of peroxisome proliferator-activated receptor ␣. PEIPC and PECPC isomers are strongly recognized by specific circulating murine natural autoantibodies (EO6) and accumulate in cells treated with IL-1␤. These studies demonstrate that PEIPC and PECPC isomers are potent activators of endothelial cells increasing synthesis of IL-8 and MCP-1. Their accumulation in cells exposed to cytokines and in atherosclerotic lesions suggests that these lipids may play a role in a number of chronic disease processes.

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“…Authentic iso [4]LGE 2 was synthesized as described and assayed by NMR ( 36 ). This compound was reacted with L-Lys to produced Lys-iso [4]LGE 2 adducts ( 37 ) which were characterized by ESI-MS/MS.…”

Section: Methodsmentioning

confidence: 99%

Posttranslational modification by an isolevuglandin diminishes activity of the mitochondrial cytochrome P450 27A1

Charvet

Laird

et al. 2013

Journal of Lipid Research

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Total Synthesis of Iso[4]-levuglandin E₂

Cited by 32 publications

References 25 publications

Structural Identification of a Novel Pro-inflammatory Epoxyisoprostane Phospholipid in Mildly Oxidized Low Density Lipoprotein

Structural Identification of a Novel Pro-inflammatory Epoxyisoprostane Phospholipid in Mildly Oxidized Low Density Lipoprotein

Epoxyisoprostane and Epoxycyclopentenone Phospholipids Regulate Monocyte Chemotactic Protein-1 and Interleukin-8 Synthesis

Posttranslational modification by an isolevuglandin diminishes activity of the mitochondrial cytochrome P450 27A1

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Total Synthesis of Iso[4]-levuglandin E2

Cited by 32 publications

References 25 publications

Structural Identification of a Novel Pro-inflammatory Epoxyisoprostane Phospholipid in Mildly Oxidized Low Density Lipoprotein

Structural Identification of a Novel Pro-inflammatory Epoxyisoprostane Phospholipid in Mildly Oxidized Low Density Lipoprotein

Epoxyisoprostane and Epoxycyclopentenone Phospholipids Regulate Monocyte Chemotactic Protein-1 and Interleukin-8 Synthesis

Posttranslational modification by an isolevuglandin diminishes activity of the mitochondrial cytochrome P450 27A1

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Total Synthesis of Iso[4]-levuglandin E₂