87173-80-6

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Uses

5'',6''-Epoxyeicosatrienoic acid is a potent vasodilator and TRPV4 agonist.

Upstream product

• 742103-77-1 6-((3Z,6Z,9Z)-1-iodopentadeca-3,6,9-trien-1-yl)tetrahydro-2Hpyran-2-one 
• 506-32-1 all cis 5,8,11,14-eicosatetraenoic acid 
• 94421-68-8 anandamide 
• 53847-30-6 2-arachidonoyl glycerol 
• 105229-01-4 (2S,3R)-3-Hydroxy-5-methoxy-tetrahydro-furan-2-carbaldehyde 
• 236743-58-1 5,6-(trans)-arachidonic acid 
• 71806-96-7 methyl-(ξ-D-arabino-2-deoxy-hexofuranoside) 
• 98050-32-9 (R)-6-((3Z,6Z,9Z)-(R)-1-Hydroxy-pentadeca-3,6,9-trienyl)-tetrahydro-pyran-2-one 
• 98050-30-7 methyl 5(R),6(R)-dihydroxyeicosatrienote 
• 154-17-6 D-2-deoxyglucose 
• 90080-06-1 methyl 5(S),6(S)-epoxyeicosatrienoate 

Relevant academic research and scientific papers

Anthracycline derivatives inhibit cardiac CYP2J2

Anthracycline chemotherapeutics are highly effective, but their clinical usefulness is hampered by adverse side effects such as cardiotoxicity. Cytochrome P450 2J2 (CYP2J2) is a cytochrome P450 epoxygenase in human cardiomyocytes that converts arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic acid (EET) regioisomers. Herein, we performed biochemical studies to understand the interaction of anthracycline derivatives (daunorubicin, doxorubicin, epirubicin, idarubicin, 5-iminodaunorubicin, zorubicin, valrubicin, and aclarubicin) with CYP2J2. We utilized fluorescence polarization (FP) to assess whether anthracyclines bind to CYP2J2. We found that aclarubicin bound the strongest to CYP2J2 despite it having large bulky groups. We determined that ebastine competitively inhibits anthracycline binding, suggesting that ebastine and anthracyclines may share the same binding site. Molecular dynamics and ensemble docking revealed electrostatic interactions between the anthracyclines and CYP2J2, contributing to binding stability. In particular, the glycosamine groups in anthracyclines are stabilized by binding to glutamate and aspartate residues in CYP2J2 forming salt bridge interactions. Furthermore, we used iterative ensemble docking schemes to gauge anthracycline influence on EET regioisomer production and anthracycline inhibition on AA metabolism. This was followed by experimental validation of CYP2J2-mediated metabolism of anthracycline derivatives using liquid chromatography tandem mass spectrometry fragmentation analysis and inhibition of CYP2J2-mediated AA metabolism by these derivatives. Taken together, we use both experimental and theoretical methodologies to unveil the interactions of anthracycline derivatives with CYP2J2. These studies will help identify alternative mechanisms of how anthracycline cardiotoxicity may be mediated through the inhibition of cardiac P450, which will aid in the design of new anthracycline derivatives with lower toxicity.

Repurposing Resveratrol and Fluconazole to Modulate Human Cytochrome P450-Mediated Arachidonic Acid Metabolism

Cytochrome P450 (P450) enzymes metabolize arachidonic acid (AA) to several biologically active epoxyeicosatrienoic acids (EETs) and hydroxyeicosatetraenoic acids (HETEs). Repurposing clinically-approved drugs could provide safe and readily available means

Endocannabinoids anandamide and 2-arachidonoylglycerol are substrates for human CYP2J2 epoxygenase

The endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are arachidonic acid (AA) derivatives that are known to regulate human cardiovascular functions. CYP2J2 is the primary cytochrome P450 in the human heart and is most well known for the metabolism of AA to the biologically active epoxyeicosatrienoic acids. In this study, we demonstrate that both 2-AG and AEA are substrates for metabolism by CYP2J2 epoxygenase in the model membrane bilayers of nanodiscs. Reactions of CYP2J2 with AEA formed four AEA-epoxyeicosatrienoic acids, whereas incubations with 2-AG yielded detectable levels of only two 2-AG epoxides. Notably, 2-AG was shown to undergo enzymatic oxidative cleavage to form AA through a NADPH-dependent reaction with CYP2J2 and cytochrome P450 reductase. The formation of the predominant AEA and 2-AG epoxides was confirmed using microsomes prepared from the left myocardium of porcine and bovine heart tissues. The nuances of the ligand-protein interactions were further characterized using spectral titrations, stopped-flow small-molecule ligand egress, and molecular modeling. The experimental and theoretical data were in agreement, which showed that substitution of the AA carboxylic acid with the 2-AG ester-glycerol changes the binding interaction of these lipids within the CYP2J2 active site, leading to different product distributions. In summary, we present data for the functional metabolomics of AEA and 2-AG by a membrane-bound cardiovascular epoxygenase.

Lipoxygenase-catalyzed transformation of epoxy fatty acids to hydroxy-endoperoxides: A potential P450 and lipoxygenase interaction

Herein, we characterize a generally applicable transformation of fatty acid epoxides by lipoxygenase (LOX) enzymes that results in the formation of a five-membered endoperoxide ring in the end product. We demonstrated this transformation using soybean LOX-1 in the metabolism of 15,16-epoxy-α-linolenic acid, and murine platelet-type 12-LOX and human 15-LOX-1 in the metabolism of 14,15-epoxyeicosatrienoic acid (14,15-EET). A detailed examination of the transformation of the two enantiomers of 15,16-epoxy-α-linolenic acid by soybean LOX-1 revealed that the expected primary product, a 13 S-hydroperoxy-15,16-epoxide, underwent a nonenzymatic transformation in buffer into a new derivative that was purifi ed by HPLC and identified by UV, LC-MS, and 1H-NMR as a 13,15-endoperoxy-16-hydroxy-octadeca-9,11-dienoic acid. The configuration of the endoperoxide (cis or trans side chains) depended on the steric relationship of the new hydroperoxy moiety to the enantiomeric configuration of the fatty acid epoxide. The reaction mechanism involves intramolecular nucleophilic substitution (SNi) between the hydroperoxy (nucleophile) and epoxy group (electrophile). Equivalent transformations were documented in metabolism of the enantiomers of 14,15-EET by the two mammalian LOX enzymes, 15-LOX-1 and platelet-type 12-LOX. We conclude that this type of transformation could occur naturally with the co-occurrence of LOX and cytochrome P450 or peroxygenase enzymes, and it could also contribute to the complexity of products formed in the autoxidation reactions of polyunsaturated fatty acids.

Stereoselective epoxidation of the last double bond of polyunsaturated fatty acids by human cytochromes P450

Cytochromes P450 (CYPs) metabolize polyun-saturated long-chain fatty acids (PUFA-LC) to several classes of oxygenated metabolites. Through use of human recombinant CYPs, we recently showed that CYP1A1, -2C19, -2D6, -2E1, and -3A4 are mainly hydroxylases, whereas CYP1A2, -2C8, -2C9, and -2J2 are mainly epoxygenases of arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), respectively. It is worth noting that the last double bond of these PUFAs, i.e., ω6 in AA or ω3 in EPA and DHA, respectively, was preferentially epoxidized. In this study, we have characterized the stereoselectivity of this epoxidation reaction by comparison with the PUFA-LC epoxide stereoisomers obtained from the enantioselective bacterial CYP102A1 F87V. The stereoselectivity of the epoxidation of the last olefi n of AA (ω6), EPA (ω3), or DHA (ω3) differed between the CYP isoforms but was similar for EPA and DHA. These data give additional insight into the PUFA-LC epoxide enantiomers generated by the hepatic CYPs. Copyright

Epoxidation of polyunsaturated fatty acid double bonds by dioxirane reagent: Regioselectivity and lipid supramolecular organization

The use of dimethyldioxirane (DMD) as the epoxidizing agent for polyunsaturated fatty acids was investigated. With fatty acid methyl esters, this is a convenient method for avoiding acidic conditions, using different solvents, and simplifying the isolation procedures, with less contamination due to by-products. The reagent was also tested with free fatty acids in water. In this case, the supramolecular organization of fatty acids influenced the reaction outcome, and the epoxidation showed interesting regioselective features. The C=C bonds closest to the aqueous-micelle interface is the most favored for the interaction with dimethyldioxirane. The preferential epoxidation of linoleic acid (=(9Z,12Z)-octadeca-9,12-dienoic acid) to the 9,10-monoepoxy derivative was achieved, with a high yield and 65% regioselectivity. In case of arachidonic acid (=(5Z,8Z,11Z,14Z)-eicosa-5,8,11,14-tetraenoic acid) micelles, the regioselective outcome with formation of the four possible monoepoxy isomers was studied under different conditions. It resulted to be a convenient synthesis of 'cis-5,6-epoxyeicosatrienoic acid' (=3-[(2Z,5Z,8Z)-tetradeca-2,5,8- trienyl]oxiran-2-butanoic acid), whereas in reverse micelles, epoxidation mostly gave 'cis-14,15-epoxyeicosatrienoic acid (= (5Z,8Z,11Z)-13-(3-pentyloxiran-2- yl)trideca-5,8,11-trienoic acid).

Stereospecific synthesis and mass spectrometry of 5,6-trans-epoxy-8Z,11Z, 14Z-eicosatrienoic acid

A novel, facile synthesis of 5,6-trans-epoxyeicosatrienoic acid (5,6-trans-EET) from 5,6-trans-arachidonic acid by iodolactonization and alkaline de-iodation is described along with characterization by mass spectrometry (LC-MS, negative ions) and NMR and comparison with 5,6-cis-EET.

Absolute Configuration of Epoxyeicosatrienoic Acids (EETs) Formed during Catalytic Oxygenation of Arachidonic Acid by Purified Rat Liver Microsomal Cytochrome P-450

Incubation of arachidonic acid with a reconstituted enzymatic system containing a purified preparation of the major, phenobarbital-inducible form of rat liver microsomal cytochrome P-450, NADPH, cytochrome b5, and NADPH-cytochrome P-450 reductase affords as the principal products four regioisomeric cis-epoxides: 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs).Their absolute configurations were established by conversion to the corresponding hydroxyeicosatetraenoic acid (HETE) methyl esters, derivatization with dehydroabiethylisocyanate, and chromatographic analysis.Except for 5,6-EET, the cytochrome P-450 catalyzed epoxidation is highly enantioselective.