六种环氧酮基十八碳烯酸（EKODE）异构体的合成，亚油酸非酶氧化生成及其与咪唑亲核试剂的反应性,The Journal of Organic Chemistry

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六种环氧酮基十八碳烯酸（EKODE）异构体的合成，亚油酸非酶氧化生成及其与咪唑亲核试剂的反应性
The Journal of Organic Chemistry ( IF 3.3 ) Pub Date : 2007-11-03 00:00:00 , DOI: 10.1021/jo701373f
De Lin ₁ , Jianye Zhang ₁ , Lawrence M. Sayre ₁

Affiliation

作为亚油酸氧化产物的一类，在体内和体外形成环氧酮十八碳烯酸（EKODEs）通过由酶促途径或非酶促途径引发的自由基机制。迄今为止，它们是由亚油酸衍生的氢过氧化物的还原分解而以小规模的形式通常以异构体混合物的形式获得的。这些化合物由于其强大的生物活性和共价修饰蛋白质的能力而引起了人们的极大兴趣。完成了六个EKODE区域和立体异构体，两个反式α'，β'-环氧-α，β-烯酮的合成，以及两个反式和两个顺式γ，δ，-环氧-α，β-烯酮的合成。关键步骤是维蒂希型反应和羟醛缩合。HPLC证实所有六种EKODE异构体都是通过掺入真实样品而在Fe（II）/抗坏血酸促进的亚油酸自氧化中生成的。Ñ ^α -benzoyl-升组氨酸与autoxidizing亚油酸和与各个EKODE异构体相比，因为是与咪唑的亲核试剂的各种EKODE反应的动力学。通过咪唑与通用EKODE-（E）-I类似物反应的NMR研究，证实了His-EKODE-（E）-I加合物的结构反映了共轭物的加成（环氧环完整无缺）。EKODE异构体的合成使这些重要分子可用于进一步的化学和生物学评估。

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Synthesis of Six Epoxyketooctadecenoic Acid (EKODE) Isomers, Their Generation from Nonenzymatic Oxidation of Linoleic Acid, and Their Reactivity with Imidazole Nucleophiles

As a class of linoleic acid oxidation products, epoxyketooctadecenoic acids (EKODEs), are formed in vivo and in vitro by a free radical mechanism initiated by either enzymatic or nonenzymatic pathways. They have so far been made available in small-scale quantities, often as isomeric mixtures, from reductive decomposition of linoleic acid-derived hydroperoxides. There is major interest in these compounds owing to their highly potent biological activities and their ability to covalently modify proteins. The synthesis of six EKODE regio- and stereoisomers, two trans α‘,β‘-epoxy-α,β-enones, and two trans and the two cis γ,δ,-epoxy-α,β-enones was accomplished, with the key steps being Wittig-type reactions and aldol condensations. All six EKODE isomers were confirmed by HPLC to be generated in the autoxidation of linoleic acid promoted by Fe(II)/ascorbic acid through spiking in of authentic samples. On the basis of evidence for EKODE modification of protein His residues, the reactions of N^α-benzoyl-l-histidine with autoxidizing linoleic acid and with the individual EKODE isomers were compared, as were the kinetics of the various EKODE reactions with imidazole nucleophiles. The structures of His-EKODE-(E)-I adducts were confirmed to reflect conjugate addition (epoxide ring remains intact) through an NMR study of the reaction of imidazole with a generic EKODE-(E)-I analog. The synthesis of the EKODE isomers makes these important molecules available for further chemical and biological evaluation.

更新日期：2007-11-03

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