Hwang Sung Hee, Wagner Karen, Xu Jian, Yang Jun, Li Xichun, Cao Zhengyu, Morisseau Christophe, Lee Kin Sing Stephen, Hammock Bruce D
Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA.
Jiangsu Provincial Key Laboratory of TCM Evaluation and Development, China Pharmaceutical University, 639, Longmian Ave, Jiangning District, Nanjing, Jiangsu 211198, PR China.
Bioorg Med Chem Lett. 2017 Feb 1;27(3):620-625. doi: 10.1016/j.bmcl.2016.12.002. Epub 2016 Dec 2.
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).
ω-羟基多不饱和脂肪酸（PUFAs）是花生四烯酸（ARA）、二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）的天然代谢产物，通过收敛合成方法制备，该方法使用两个关键步骤：铜介导的碳-碳键形成以构建亚甲基间隔的多炔，以及部分炔烃氢化，其中过量的2-甲基-2-丁烯作为添加剂的存在被证明对于多炔部分还原为相应的顺式烯烃且不过度氢化的成功至关重要。在未处理的大鼠中评估了ω-羟基PUFAs在疼痛方面的潜在生物学功能。在足底注射后，20-羟基二十碳四烯酸（20-HETE，ω-羟基ARA）在机械伤害感受试验中导致爪退缩阈值急性降低，表明疼痛，但接受20-羟基二十碳五烯酸（20-HEPE，ω-羟基EPA）或22-羟基二十二碳六烯酸（22-HDoHE，ω-羟基DHA）的大鼠未观察到变化。我们还发现，20-HEPE和22-HDoHE在激活小鼠瞬时受体电位香草酸受体1（mTRPV1）方面比20-HETE更有效。
