Prostaglandin endoperoxides. 25. Levuglandin E2: enantiocontrolled total synthesis of a biologically active rearrangement product from the prostaglandin endoperoxide PGH2

Miller, Donald B.; Raychaudhuri, Sarmistha Sen; Avasthi, Kamlakar; Lal, K.; Levison, Bruce S.; Salomon, Robert G.

doi:10.1021/jo00297a036

Cited by 34 publications

(48 citation statements)

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“…As predicted by the model studies, nonenzymatic rearrangements of PGH 2 generate two isomeric levulinaldehyde derivatives with prostaglandin side chains that we named levuglandins, that is, LGE 2 and LGD 2 (Scheme 1). 4 A total synthesis of LGE 2 confirmed its structure 5…”

Section: Rearrangement Of Endoperoxides To Levulinaldehydesmentioning

confidence: 82%

Isolevuglandins, Oxidatively Truncated Phospholipids, and Atherosclerosis

Salomon

2005

Annals of the New York Academy of Sciences

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Isolevuglandins (isoLGs) and oxidatively truncated phospholipids are products of lipid peroxidation. Some of these, especially isoLGs and gamma-hydroxyalkenal analogues (e.g., the 5-hydroxy-8-oxo-6-octenoic acid and 9-hydroxy-12-oxo-10-dodecenoic acid esters of 2-lysophosphatidylcholine, HOOA-PC or HODA-PC, respectively) of 4-hydroxy-2(E)-nonenal (HNE), damage proteins by covalent adduction, thereby interfering with their normal functions. These lipid-derived protein modifications may serve as dosimeters of oxidative injury. Elevated plasma levels of isoLG-protein epitopes are associated with atherosclerosis but are independent of total cholesterol, a classical risk factor. Both protein adducts and oxidatively truncated phospholipids (oxPL) can also elicit receptor-mediated cellular responses that include endocytosis of oxidized low-density lipoprotein (LDL) and expression of chemokines, which may foster infiltration of monocyte macrophages into the subendothelial space, where they become foam cells through unregulated endocytosis of oxidatively damaged LDL.

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Section: Rearrangement Of Endoperoxides To Levulinaldehydesmentioning

confidence: 82%

Isolevuglandins, Oxidatively Truncated Phospholipids, and Atherosclerosis

Salomon

2005

Annals of the New York Academy of Sciences

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“…This solution was diluted 20 times as needed. LGE 2 (34), iso [4]LGE 2 (35), and 4-oxopentanal-BSA (36) were prepared as described previously. LDL was isolated (37) from human plasma and oxidized in vitro to give oxLDL as described previously (27).…”

Section: Methodsmentioning

confidence: 99%

Protein Adducts of Iso[4]levuglandin E2, a Product of the Isoprostane Pathway, in Oxidized Low Density Lipoprotein

Salomon

Wang

Brame

et al. 1999

Journal of Biological Chemistry

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Levuglandin (LG) E 2 , a cytotoxic seco prostanoic acid co-generated with prostaglandins by nonenzymatic rearrangements of the cyclooxygenase-derived endoperoxide, prostaglandin H 2 , avidly binds to proteins. That LGE 2 -protein adducts can also be generated nonenzymatically is demonstrated by their production during free radical-induced oxidation of low density lipoprotein (LDL). Like oxidized LDL, LGE 2 -LDL, but not native LDL, undergoes receptor-mediated uptake and impaired processing by macrophage cells. Since radicalinduced lipid oxidation produces isomers of prostaglandins, isoprostanes (isoPs), via endoperoxide intermediates, we postulated previously that a similar family of LG isomers, isoLGs, is cogenerated with isoPs. Now iso[4]LGE 2 -protein epitopes produced by radicalinduced oxidation of arachidonic acid in the presence of protein were detected with an enzyme-linked immunosorbent assay. Iso[4]LGE 2 -protein epitopes are also generated during free radical-induced oxidation of LDL. All of the LGE 2 isomers generated upon oxidation of LDL are efficiently sequestered by covalent adduction with LDL-based amino groups. The potent electrophilic reactivity of iso-LGs can be anticipated to have biological consequences beyond their obvious potential as markers for specific arachidonate-derived protein modifications that may be of value for the quantitative assessment of oxidative injury.

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“…The IsoK enclosed in the box in Fig. 1 was obtained from a 15-R,S epimeric mixture of the methyl ester, O-tert-butyl-dimethylsilyl ether, an isopropylidine precursor (11). The IsoK (1 M) was incubated with [ 3 H 2 , 13 C 6 ]lysine (3.5 ϫ 1014 dpm/mol) for 1 h in phosphate-buffered saline.…”

Section: Preparation and Analysis Of Rat Liver Proteins-malementioning

confidence: 99%

Modification of Proteins by Isoketal-containing Oxidized Phospholipids

Brame¹,

Boutaud

Davies

et al. 2004

Journal of Biological Chemistry

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Oxidative stress frequently leads to altered function of membrane proteins. Isoketals are highly reactive products of the isoprostane pathway of free radical-induced lipid peroxidation that rapidly form covalent protein adducts and exhibit a remarkable proclivity to form protein cross links in vitro. Examination of isoketal adducts from an animal model of oxidative injury revealed that initial adducts were formed by isoketals esterified in phospholipids, representing a novel oxidative injuryassociated modification of proteins by phospholipids. Maturation of adducts involved cleavage from phospholipids and conversion of adducts to a more stable chemical form that can be detected for extended periods. Because initial adducts were formed by phospholipidesterified isoketals, the functional consequence of isoketal adduction was examined using a model membrane protein (a cardiac K ؉ channel). These studies revealed that isoketal adduction profoundly altered protein function, inhibiting potassium current in a dosedependent manner. These findings indicate that phospholipid-esterified isoketals rapidly adduct membrane proteins and that such modification can alter protein function, suggesting a generalized cellular mechanism for alteration of membrane function as a consequence of oxidative stress.Oxidative stress from the generation of free radicals has been implicated in the pathogenesis of a wide variety of human diseases including atherosclerosis, cancer, and neurodegenerative diseases (1-3). Fatty acids esterified in membrane phospholipids are a major target of attack by free radicals (4 -6). We have described previously the formation of a series of highly electrophilic ␥-ketoaldehyde isomers in vitro, which we term isoketals (IsoKs) 1 (7), by rearrangement of endoperoxide intermediates in the isoprostane pathway of free radical-induced peroxidation of phospholipid-esterified arachidonic acid (8). Incorporation of oxygen at different sites of arachidonyl radical formation results in the formation of 8 structural isomers, each of which is composed of 4 racemic diastereoisomers (see Fig. 1A). Analogous molecules, termed neuroketals, are formed from the free radical-catalyzed oxidation of docosahexanoic acid and form protein adducts analogous to those described below for IsoKs (9).IsoKs adduct covalently with the ⑀-amino group of lysine residues in vitro within seconds, which is orders of magnitude faster than has been reported for other products of lipid peroxidation, including 4-hydroxynonenal (7). This remarkable reactivity has precluded the detection of free IsoKs in vivo because of their sequestration as adducts. Therefore, we elucidated the nature of IsoK protein adducts in vitro as an initial step toward identifying the formation of IsoK adducts in vivo (7, 10). IsoKs initially form reversible Schiff base adducts which irreversibly cyclize to pyrroles. The pyrroles then undergo facile autoxidation to stable lactam and hydroxylactam adducts (see Fig. 1B) (7, 10). Consistent with this process, Schiff base adducts f...

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Prostaglandin endoperoxides. 25. Levuglandin E2: enantiocontrolled total synthesis of a biologically active rearrangement product from the prostaglandin endoperoxide PGH2

Cited by 34 publications

References 0 publications

Isolevuglandins, Oxidatively Truncated Phospholipids, and Atherosclerosis

Isolevuglandins, Oxidatively Truncated Phospholipids, and Atherosclerosis

Protein Adducts of Iso[4]levuglandin E2, a Product of the Isoprostane Pathway, in Oxidized Low Density Lipoprotein

Modification of Proteins by Isoketal-containing Oxidized Phospholipids

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