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. 2017 Feb 1;27(3):620-625.
doi: 10.1016/j.bmcl.2016.12.002. Epub 2016 Dec 2.

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

Sung Hee Hwang  1 , Karen Wagner  1 , Jian Xu  2 , Jun Yang  1 , Xichun Li  2 , Zhengyu Cao  2 , Christophe Morisseau  1 , Kin Sing Stephen Lee  1 , Bruce D Hammock  3
Affiliations

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

Sung Hee Hwang et al. Bioorg Med Chem Lett. .

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 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).

Keywords: 20-HEPE; 20-HETE; 22-HDoHE; Pain; TRPV1; ω-Hydroxy PUFA.

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Figures

Figure 1
Figure 1
Comparison of pain induction by ω-hydroxy PUFAs, 20-HETE, 20-HEPE, and 22-HDoHE, in naïve rats. (A) Intraplantar injection of the corresponding methyl esters (1 µg in 1:9 EtOH/saline) revealed ω-6 hydroxy PUFA (20-HETE), but not ω-3 hydroxy PUFAs (20-HEPE and 22-HDoHE), changed mechanical withdrawal sensitivity in the von Frey assay (Two Way Analysis of Variance, Holm-Sidak post hoc p < 0.001, n = 6, male Sprague Dawley rats). (B) Intraplantar injection of 20-HETE (1 µg of 20-HETE methyl ester in 1:9 EtOH/saline) decreased mechanical withdrawal thresholds in a dose-dependent manner indicating that pain behavior was localized to the injected (ipsilateral) hind paw (Two Way Analysis of Variance, Holm-Sidak post hoc p = 0.005, n = 6, male Sprague Dawley rats).
Figure 2
Figure 2
Calcium influx assay. (A) Capsaicin, 20-HETE, 20-HEPE and 22-HDoHE-induced Ca2+ influx in mTRPV1-transfected HEK293 cells as a function of time. (B) Quantification of the Ca2+ responses (area under curve, AUC) induced by capsaicin, 20-HETE, 20-HEPE and 22-HDoHE. The experiments were repeated twice each in triplicates with similar results.
Scheme 1
Scheme 1
Synthetic routes of compounds 20-HETE, 20-HEPE, and 22-HDoHE. Reagents and conditions: (a) CuI, NaI, Cs2CO3, 4-chloro-2-butyn-1-ol, DMF, rt, 12h; (b) PPh3, CBr4, DCM, 0 °C, 2h; (c) CuI, NaI, Cs2CO3, 3-bromo-1-(trimethylsilyl)-1-propyne, DMF, rt, 12h; (d) 1M TBAF in THF, AcOH, THF, rt, 12h; (e) Et3N, DMAP, p-TsCl, DCM, 0 °C to rt, 12h; (f) CuI, NaI, Cs2CO3, 3-butyn-1-OH, DMF, rt, 12h; (g) CuI, NaI, Cs2CO3, propargyl alcohol, DMF, rt, 12h; (h) CuI, NaI, Cs2CO3, DMF, rt, 12h; (i) Lindlar catalyst, 2-methyl-2-butene:MeOH:pyridine (4:4:1), H2, rt, 18h-2d (note: 1:1 MeOH/EtOAc was used instead of MeOH for both 20 and 22); (j) 1N NaOH, MeOH, rt, 5h.
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