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

Abstract

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 C-C 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).

Adaptive thermogenesis by dietary n-3 polyunsaturated fatty acids: Emerging evidence and mechanisms

“…This agrees with literature suggesting that n-3 PUFA are better ligands for GPR120 than n-6 PUFA [22]. Moreover, these data are consistent with recent results that metabolites of n-3 PUFA are much more potent agonists for the TRPV1 receptor than metabolites of ARA [55]. N-3 PUFA seemingly exhibit distinctive mechanisms on brown vs. beige precursor cells, although GPR120 is involved in both brown and beige fat development.…”

20‐hydroxyeicosatetraenoic acid (20‐HETE) is a pivotal endogenous ligand for TRPV1‐mediated neurogenic inflammation in the skin

“…Hwang et al (2000) compared the activation of TRPV1 of several endogenous arachidonic acid metabolites and found that the strongest endogenous activator was 12-HpETE, which is formed by 12-LOX. Our own research compared 12-HpETE with 20-HETE and identified it as an even more potent TRPV1 agonist (Bubb et al, 2013;Kroetz & Xu, 2005;Wen et al, 2012) and others have confirmed our observations that 20-HETE acts as a TRPV1 agonist (Hwang et al, 2017;Wang et al, 2020;Zhang et al, 2018). However, whether 20-HETE via activation of TRPV1 is a pivotal ligand for the channel in the setting of inflammation is unknown.…”

TRPV1: Structure, Endogenous Agonists, and Mechanisms

“…In this way, linoleic acid (LA 18:2) serves as a precursor to several other molecules such as arachidonic acid (AA 20:4) [47]. Then, this is followed by hydroxylation or epoxidation reactions catalyzed by cytochrome P450 (CYP450) enzymes, resulting in the generation of hydroxyeicosatetraenoic acids (HETEs), such as 20-hydroxyeicosatetraenoic acid (20-HETE), or epoxieicosatrienoic acids (EETs) [49,50] (Figure 2).…”

“…α-linolenic acid (ALA 18:3) produces eicosapentaenoic acid (EPA 20:5) and docosahexaenoic acid (DHA 22:6) [47], which are precursors of 20-hydroxyeicosapentaenoic acid (20-HEPE) and 22-hydroxyeicosapentaenoic acid (22-HDoHE) [50] (Figure 3). α-linolenic acid (ALA 18:3) produces eicosapentaenoic acid (EPA 20:5) and docosahexaenoic acid (DHA 22:6) [47], which are precursors of 20-hydroxyeicosapentaenoic acid (20-HEPE) and 22hydroxyeicosapentaenoic acid (22-HDoHE) [50] (Figure 3).…”