Stereochemical assignment and anti-inflammatory properties of the omega-3 lipid mediator resolvin E3
Stereochemical assignment and anti-inflammatory properties of the omega-3 lipid mediator resolvin E3
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DOI：
10.1093/jb/mvs151
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发表时间：
2013-04-01
影响因子：
2.7
通讯作者：
Arai, Hiroyuki
中科院分区：
文献类型：
--
作者：
Isobe, Yosuke;Arita, Makoto;Arai, Hiroyuki
不受控制的炎症现在被认为是许多广泛发生的疾病之间的联系。因此，控制先天炎症反应及其局部化学介质受到越来越多的关注。我们最近发现了一个由嗜酸性粒细胞产生的二十碳五烯酸(EPA)衍生的新的介体家族，称为解决素E3(RvE3)，它在体外和体内都具有强大的抗炎作用。17位和18位的碳是不对称的，因此该分子总共有四个潜在的立体异构体。在这里，我们指定了RvE3的两个天然异构体和四个不同的立体异构体中的醇的共轭双键和手性的立体化学。RvE3的两个天然异构体的完整结构分别为17R，18S-和17R，18R-二羟基-5Z，8Z，11Z，13E，15E-EPA。这些通过全有机合成制备的天然异构体在体外和体内都通过限制中性粒细胞的渗透而显示出强大的抗炎作用。与天然异构体相比，非天然立体异构体的活性要低得多，说明RvE3具有立体选择性作用。
Uncontrolled inflammation is now considered to be a link between many widely occurring diseases. Thus, controlling the innate inflammatory response and its local chemical mediators has been receiving increasing attention. We recently identified a novel family of eicosapentaenoic acid (EPA)-derived mediators produced by eosinophils, denoted as resolvin E3 (RvE3), that possess potent anti-inflammatory actions both in vitro and in vivo. Carbons at 17 and 18 positions are asymmetric and thus the molecule has a total of four potential stereoisomers. Here, we assigned the stereochemistry of the conjugated double bonds and chirality of alcohols present in two natural isomers of RvE3 with four different stereoisomers prepared by total organic synthesis. The complete structures of two natural isomers of RvE3 were determined to be 17R,18S- and 17R,18R-dihydroxy-5Z,8Z,11Z,13E,15E-EPA, respectively. These natural isomers prepared by total organic synthesis displayed a potent anti-inflammatory action by limiting neutrophil infiltrations both in vitro and in vivo. The unnatural stereoisomers were much less active compared with the natural isomers, demonstrating the stereoselective action of RvE3.