Chemical synthesis and biological evaluation of ω-hydroxy polyunsaturated fatty acids

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• 作者：Sung Hee Hwang^a ; Karen Wagner^a ; Jian Xu^b ; Jun Yang^a ; Xichun Li^b ; Zhengyu Cao^b ; Christophe Morisseau^a ; Kin Sing Stephen Lee^a ; Bruce D. Hammock^a ; ^{bdhammock@ucdavis.edu}
• 关键词：ARA ; arachidonic acid ; COX ; cyclooxygenase ; CYP 450 ; cytochrome P450 ; DHA ; docosahexaenoic acid ; EPA ; eicosapentaenoic acid ; FLIPR ; fluorescent imaging plate reader ; 22-HDoHE ; 22-hydroxydocosahexaenoic acid ; 20-HEPE ; 20-hydroxyeicosapentaenoic acid ; 20-HETE ; 20-hydroxyeicosatetranoic acid ; PUFA ; polyunsaturated fatty acids ; TRPV1 ; transient receptor potential vanilloid 1
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：27
• 期：3
• 页码：620-625
• 全文大小：922 K
• 卷排序：27

文摘

ω-Hydroxy polyunsaturated fatty acids (PUFAs), natural metabolites from arachidonic acid (ARA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were prepared via convergent synthesis approach using two key steps: Cu-mediated CC bond formation to construct methylene skipped poly-ynes and a partial alkyne hydrogenation where the presence of excess 2-methyl-2-butene as an additive that is proven to be critical for the success of partial reduction of the poly-ynes to the corresponding cis-alkenes without over-hydrogenation. The potential biological function of ω-hydroxy PUFAs in pain was evaluated in naive rats. Following intraplantar injection, 20-hydroxyeicosatetraenoic acid (20-HETE, ω-hydroxy ARA) generated an acute decrease in paw withdrawal thresholds in a mechanical nociceptive assay indicating pain, but no change was observed from rats which received either 20-hydroxyeicosapentaenoic acid (20-HEPE, ω-hydroxy EPA) or 22-hydroxydocosahexaenoic acid (22-HDoHE, ω-hydroxy DHA). We also found that both 20-HEPE and 22-HDoHE are more potent than 20-HETE to activate murine transient receptor potential vanilloid receptor1 (mTRPV1).