Arachidonic acid epoxidation

N. Chacos, J. Capdevilla, J. R. Falck, S. Manna, C. Martin-Wixtrom, S. S. Gill, B. D. Hammock, R. W. Estabrook, The Reaction of Arachidonic Acid Epoxides (Epoxyeico-satrienoic Acids) with a Cytosolic Epoxide Hydrolase , Arch. Biochem. Biophys. 1983, 223, 639 - 648. 

Brand-Schieber, E., J.F. Falck, and M. Schwartzman (2000). Selective inhibition of arachidonic acid epoxidation in vivo. J. Physiol. Pharmacol. 51, 655-672. 

Chacos N, Capdevila J, Falck JR, Manna S, Martin-Wixtrom C, Gill SS, Hammock BD, Estabrook, RW (1983) The reaction of arachidonic acid epoxides (epoxyeicosatrienoic acids) with a cytosolic epoxide hydrolase. Arch Biochem Biophys 223 639-648... 

Pace-Asciak CR, Granstr5m E, Samuelsson B. Arachidonic acid epoxides. Isolation and structure of two hydroxyepoxide intermediates in the formation of 8,11,12 and 10,11,12-trihydroxy-eicosatrienoic acids. J Biol Chem 1983 258 6835-6840. 

This remarkably selective internal epoxidation of peroxyarachidonic acid to form 14,15-oxido-arachidonic acid occurs as shown because of unusually favorable stereoelectronics. The corresponding reaction sequence with eicosa-(E)-8,ll,14-trienoic acid affords the Ai4,i5 epoxide in 94% isolated yield and >95% purity. 

Table I. Relative Yields of Diastereomeric Adducts From Anti-diol Epoxide Plus Polyguanylic Acid Compared to Adducts Generated During Metabolism of BP-7,8-dihydrodiol by Ram Seminal Vesicles in the Presence of Arachidonic Acid...

Peroxyl radicals are the species that propagate autoxidation of the unsaturated fatty acid residues of phospholipids (50). In addition, peroxyl radicals are intermediates in the metabolism of certain drugs such as phenylbutazone (51). Epoxidation of BP-7,8-dihydrodiol has been detected during lipid peroxidation induced in rat liver microsomes by ascorbate or NADPH and during the peroxidatic oxidation of phenylbutazone (52,53). These findings suggest that peroxyl radical-mediated epoxidation of BP-7,8-dihydrodiol is general and may serve as the prototype for similar epoxidations of other olefins in a variety of biochemical systems. In addition, peroxyl radical-dependent epoxidation of BP-7,8-dihydrodiol exhibits the same stereochemistry as the arachidonic acid-stimulated epoxidation by ram seminal vesicle microsomes. This not only provides additional... 

Schreiber s model has also proved to be a general approach to a series of oxygenated metabolites of arachidonic acid, such as lipoxin A and lipoxin B.50 The family of linear oxygenated metabolites of arachidonic acid has been implicated in immediate hypersensitivity reactions, inflammation, and a number of other health problems. Among these metabolites, several compounds, such as lipoxin A, lipoxin B, 5,6-diHETE, and 14,15-diHETE possess 1-substituted (/ )-1 -alken-3.4-diol 84 as a common substructural moiety. Therefore, the car-binol 83 is an ideal substrate for generating compound 84 by applying Sharpless epoxidation reaction.50... 

Polyunsaturated fatty acids in general and arachidonic acid in particular are especially of interest. With its four C=C bonds, arachidonic acid (10.51) can be oxidized by cytochrome P450 to four regioisomeric monoepoxides, namely the epoxyeicosatrienoic acids (EETs). The four epoxides, although chemically stable, were shown to be hydrolyzed to the corresponding vicinal diols by mouse liver cytosolic EH but not by microsomal EH... 

Eicosanoid synthesis. Arachidonic acid is converted by cyclooxygenases into prostaglandins, and thromboxanes. Lipoxygenases convert arachidonic acid into HPETEs, which are then converted to lipoxins, leukotrienes, and 12-HETE (hydroxyeicosatetraenoic acid). Epoxygenases convert arachidonic acid into epoxides. 

Conversion of bromohydrins to alkenes. The 14,15-epoxide (1) of arachidonic acid methyl ester has been converted into the 11,12-epoxide (5) in two steps. The first is conversion of 1 into a mixture of isomeric bromohydrins (2 and 3) with KBr. The mixture is then epoxidized under the conditions of Sharplcss (5, 75 76) to give, after chromatographic purification, 4, the epoxide of 2. Conversion of 4 into 5 presented a problem, but was eventually achieved by treatment of the w c-bromo Inflate with P[N(CHj)2]j as a Br acceptor. 

The roles of leukotrienes and cytochrome P450 products in the human kidney are currently speculative. Recently, the 5,6-epoxide has been shown to be a powerful vasodilator in animal experiments. Another recent discovery is that free radicals attack arachidonic acid-containing phospholipids to yield an 8-ep/-PGF2[J that has powerful thromboxane-like properties. Synthesis is not blocked by COX inhibitors but can be blocked by antioxidants. This vasoconstrictor, which is present in humans, is thought to be another important mediator causing renal failure in the hepatorenal syndrome. 

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