8,9-epoxyeicosa-5(Z),11(Z),14(Z)-trienoic acid | 184488-44-6

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: 8,9-epoxyeicosa-5(Z),11(Z),14(Z)-trienoic acid
• 英文别名: 8,9-Epoxyeicosatrienoic acid；8,9-EET；8,9-epoxy-5Z,11Z,14Z-eicosatrienoic acid；(±)8,9-epoxy-5Z,11Z,14Z-eicosatrienoic acid；(Z)-7-[3-[(2Z,5Z)-undeca-2,5-dienyl]oxiran-2-yl]hept-5-enoic acid
• CAS: 184488-44-6
• 化学式: C₂₀H₃₂O₃
• 分子量: 320.472
• InChiKey: DBWQSCSXHFNTMO-TYAUOURKSA-N

物化性质

• 沸点：
  456.2±20.0 °C(Predicted)
• 密度：
  0.983±0.06 g/cm3(Predicted)
• 物理描述：
  Solid

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  23
• 可旋转键数：
  14
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  49.8
• 氢给体数：
  1
• 氢受体数：
  3

ADMET

代谢

8,9-EET是花生四烯酸的已知人类代谢物。

8,9-EET is a known human metabolite of arachidonic acid.

来源:NORMAN Suspect List Exchange

反应信息

• 作为反应物：
  描述：

  8,9-epoxyeicosa-5(Z),11(Z),14(Z)-trienoic acid 在 还原型辅酶II(NADPH)四钠盐 作用下， 以 水 为溶剂， 反应 0.5h， 生成 18-hydroxy-8,9-epoxyeicosa-5(Z),11(Z),14(Z)-trienoic acid
  参考文献：
  名称：

  LC–MS/MS analysis of epoxyalcohols and epoxides of arachidonic acid and their oxygenation by recombinant CYP4F8 and CYP4F22

  摘要：

  CYP4F22 and CYP4F8 are expressed in epidermis, and mutations of CYP4F22 are associated with lamellar ichthyosis. Epoxyalcohols (HEETs) and epoxides (EETs) of 20:4n-6 appear to be important for the water permeability barrier of skin. Our aim was to study the MS/MS spectra and fragmentation of these compounds and to determine whether they were oxidized by CYP4F22 or CYP4F8 expressed in yeast. HEETs were prepared from 1 5-hydroperoxyeicosatetraenoic acid (15-HPETE), 12-HPETE, and their- [H-2(8)]labeled isotopomers, and separated by normal phase-HPLC with MS/MS analysis. CYP4F22 oxygenated 20:4n-6 at C-I 8, whereas metabolites of HEETs could not be identified. CYP4F8 formed omega 3 hydroxy metabolites of HEETs derived from 12R-HPETE with 11,12-epoxy-10-hydroxy configuration, but not HEETs derived from 15S-HPETE. 8,9-EET and 11,12-EET were also subject to omega 3 hydroxylation by CYP4F8. We conclude that CYP4F8 and CYP4F22 oxidize 20:4n-6 and that CYP4F8 selectively oxidizes 8,9-EET, 11,12-EET, and 10, 11R, 12R-HEET at the omega 3 position. (C) 2010 Published by Elsevier Inc.

  DOI：

  10.1016/j.abb.2009.11.013
• 作为产物：
  描述：

  花生四烯酸 在 cytochrome P₄₅₀ enzyme 作用下， 生成 8,9-epoxyeicosa-5(Z),11(Z),14(Z)-trienoic acid
  参考文献：
  名称：

  Maternal glyphosate exposure causes autism-like behaviors in offspring through increased expression of soluble epoxide hydrolase

  摘要：

  母体暴露于高浓度除草剂草甘膦可能会增加后代患自闭症谱系障碍（ASD）的风险；然而，相关机制仍然大部分未知。孕期和哺乳期母体暴露于草甘膦会导致小鼠雄性后代出现类似ASD的行为异常和肠道微生物组成异常。母体暴露于草甘膦后，后代大脑中的可溶性环氧化酶（sEH）比对照组更高。从怀孕到断奶期间使用sEH抑制剂治疗可以预防母体暴露于草甘膦后后代出现类似ASD的行为异常。这里使用的草甘膦暴露超过任何合理的饮食、环境或职业暴露，但它们表明增加的sEH在后代的ASD样行为中起作用。

  DOI：

  10.1073/pnas.1922287117

文献信息

• Endocannabinoids Anandamide and 2-Arachidonoylglycerol Are Substrates for Human CYP2J2 Epoxygenase
  作者：Daniel R. McDougle、Amogh Kambalyal、Daryl D. Meling、Aditi Das

  DOI：10.1124/jpet.114.216598

  日期：2014.12

  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.

  内源性大麻素，阿南达胺（AEA）和2-花生四烯酸甘油酯（2-AG），是已知能调节人类心血管功能的花生四烯酸（AA）衍生物。CYP2J2是人类心脏中的主要细胞色素P450，最为人知的是将AA代谢为生物活性环氧二十烯酸。在本研究中，我们表明2-AG和AEA都是CYP2J2环氧化酶在纳米盘膜模型中代谢的底物。CYP2J2与AEA的反应形成了四种AEA-环氧二十烯酸，而与2-AG的孵育仅产生可检测到的两种2-AG环氧化物。值得注意的是，2-AG在CYP2J2和细胞色素P450还原酶的NADPH依赖反应下，显示出经历酶促氧化裂解，形成AA。通过使用从猪和牛心脏左心肌样本制备的微粒体，确认了主要AEA和2-AG环氧化物的形成。我们进一步通过光谱滴定、停止流小分子配体逸出和分子建模来表征配体-蛋白质相互作用的细微差别。实验和理论数据一致，表明用2-AG酯甘油替代AA羧酸改变了这些脂质在CYP2J2活性位点内的结合相互作用，从而导致不同的产物分布。总之，我们提供了关于膜结合的心血管环氧化酶对AEA和2-AG的功能代谢组学的数据。
• Lipoxygenase-catalyzed transformation of epoxy fatty acids to hydroxy-endoperoxides: a potential P450 and lipoxygenase interaction
  作者：Tarvi Teder、William E. Boeglin、Alan R. Brash

  DOI：10.1194/jlr.m054072

  日期：2014.12

  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 13S-hydroperoxy-15,16-epoxide, underwent a nonenzymatic transformation in buffer into a new derivative that was purified 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

  在此，我们描述了脂氧合酶 (LOX) 对脂肪酸环氧化物的普遍适用转化，该转化导致最终产品中形成五元内过氧化物环。我们在 15,16-环氧-α-亚麻酸代谢中使用大豆 LOX-1 以及在 14,15-环氧二十碳三烯酸代谢中使用鼠血小板型 12-LOX 和人 15-LOX-1 证明了这种转化。 14,15-EET）。对大豆 LOX-1 对 15,16-环氧-α-亚麻酸的两种对映异构体的转化进行的详细检查表明，预期的主要产物 13S-氢过氧-15,16-环氧化物在缓冲液中经历了非酶促转化转化为一种新的衍生物，经 HPLC 纯化，经 UV、LC-MS 和 1H-NMR 鉴定为 13,15-endoperoxy-16-hydroxy-octadeca-9,11-dienoic acid。内过氧化物的构型（顺式或反式侧链）取决于新的氢过氧部分与脂肪酸环氧化物的对映体构型的空间关系。反应机理涉及氢过氧（亲
• Epoxidation of Polyunsaturated Fatty Acid Double Bonds by Dioxirane Reagent: Regioselectivity and Lipid Supramolecular Organization
  作者：Stanislav A. Grabovskiy、Natalia N. Kabal'nova、Chryssostomos Chatgilialoglu、Carla Ferreri

  DOI：10.1002/hlca.200690209

  日期：2006.10

  reaction outcome, and the epoxidation showed interesting regioselective features. The CC 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

  研究了使用二甲基二环氧乙烷（DMD）作为多不饱和脂肪酸的环氧化剂。对于脂肪酸甲酯，这是一种避免酸性条件，使用不同溶剂并简化分离步骤，减少副产物污染的简便方法。还用水中的游离脂肪酸测试了该试剂。在这种情况下，脂肪酸的超分子组织影响了反应结果，并且环氧化显示出有趣的区域选择性特征。最接近水-胶束界面的CC键最适合与二甲基二环氧乙烷相互作用。亚油酸的优先环氧化（=（9 Z，12 Z）-（十八烷基-9,12-二烯酸）生成9,10-单环氧衍生物，具有高收率和65％的区域选择性。在花生四烯酸（=（5 Z，8 Z，11 Z，14 Z）-二十碳五，8,11,14-四烯酸）胶束的情况下，在以下条件下研究了形成四种可能的单环氧异构体的区域选择性结果不同的条件。结果是'顺式-5,6-环氧二十碳三烯酸'（= 3-[（2 Z，5 Z，8 Z）-十四烷基-2,5,8-三烯基]环氧乙烷-2-丁酸的简便合成方法），而在反
• Repurposing Resveratrol and Fluconazole To Modulate Human Cytochrome P450-Mediated Arachidonic Acid Metabolism
  作者：Ahmed A. El-Sherbeni、Ayman O. S. El-Kadi

  DOI：10.1021/acs.molpharmaceut.5b00873

  日期：2016.4.4

  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 to control EETs and HETEs levels in humans. Our aim was to determine how to significantly and selectively modulate P450-AA metabolism in humans by

  细胞色素P450（P450）酶将花生四烯酸（AA）代谢为几种具有生物活性的环氧二十碳三烯酸（EET）和羟基二十碳四烯酸（HETE）。重新使用经过临床批准的药物可以为控制人类中的EET和HETE水平提供安全且容易获得的手段。我们的目标是确定如何通过临床批准的药物显着和选择性地调节人体内的P450-AA代谢。液相色谱-质谱法用于测定人重组P450酶以及人肝和肾微粒体形成的15种AA代谢产物。CYP2C19显示最高的EET形成活性，而CYP1B1和CYP2C8显示最高的中链HETE形成活性。CYP1A1和CYP4分别显示出最高的亚末端和20-HETE形成活性。与研究药物相比，白藜芦醇和氟康唑对肝P450-AA代谢产生了最有选择性和最显着的调节作用。蒙特卡洛模拟显示，每天服用2.5克后，有90％的人口在16-，18-和20-HETE形成中分别减少6-22％，16-39％和16-35％。白藜芦醇，氟康唑50
• Use of cis-Epoxyeicosantrienoic acids and inhibitors of soluble epoxide hydrolase to reduce pulmonary infiltration by neutrophils
  申请人：Hammock D. Bruce

  公开号：US20050222252A1

  公开（公告）日：2005-10-06

  It has now been discovered that inhibitors of soluble epoxide hydrolase (“sEH”) are useful in reducing the severity of or inhibiting the progression of obstructive pulmonary diseases, restrictive airway diseases, and asthma. Administering a cis-epoxyeicosantrienoic acid (“EET”) in addition to the inhibitor is at least additive, and may be synergistic, in reducing or inhibiting these conditions and diseases, as measured by reduced numbers of neutrophils present in the lung. The inhibitor of sEH may be a nucleic acid, such as a small interfering RNA.

  现在已经发现，可溶性环氧酰胺水解酶（“sEH”）的抑制剂对于减轻或抑制阻塞性肺疾病、限制性气道疾病和哮喘的严重程度是有用的。在抑制剂的基础上给予顺式环氧二十碳五烯酸（“EET”）至少是具有相加作用的，并且可能具有协同作用，可通过减少肺部中嗜中性粒细胞数量来减轻或抑制这些状况和疾病。sEH的抑制剂可能是核酸，例如小干扰RNA。