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Enzymatic Synthesis of Epoxidized Metabolites of Docosahexaenoic, Eicosapentaenoic, and Arachidonic Acids
Published on: June 28, 2019
Inhibition effect of 1-acetoxy-6α-(2-methylbutyryl)eriolanolide toward soluble epoxide hydrolase: Multispectral
Juan Zhang1, Fang-Yu Yang2, Qi-Meng Zhu3
1College of Pharmacy, Dalian Medical University, Dalian, China; School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, China.
Abstract:
Soluble epoxide hydrolase (sEH) serves as a potential target in inflammation-related diseases. Based on the bioactivity-guided separation, a new sesquiterpenoid inulajaponoid A (1) was isolated from Inula japonica with a sEH inhibitory effect, together with five known compounds, such as 1-O-acetyl-6-O-isobutyrylbritannilactone (2), 6β-hydroxytomentosin (3), 1β,8β-dihydroxyeudesma-4(15),11(13)-dien-12,6α-olide (4), (4S,6S,7S,8R)-1-O-acetyl-6-O-(3-methylvaleryloxy)-britannilactone (5), and 1-acetoxy-6α-(2-methylbutyryl)eriolanolide (6). Among them, compounds 1 and 6 were assigned as mixed and uncompetitive inhibitors, respectively. The result of immunoprecipitation (IP)-MS demonstrated the specific binding of compound 6 to sEH in the complex system, which was further confirmed by the fluorescence-based binding assay showing its equilibrium dissociation constant (Kd = 2.43 μM). The detail molecular stimulation revealed the mechanism of action of compound 6 with sEH through the hydrogen bond of amino acid residue Gln384. Furthermore, this natural sEH inhibitor (6) could suppress the MAPK/NF-κB activation to regulate inflammatory mediators, such as NO, TNF-α, and IL-6, which confirmed the anti-inflammatory effect of inhibition of sEH by 6. These findings provided a useful insight to develop sEH inhibitors upon the sesquiterpenoids.
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