Coumarins Isolated from Murraya paniculata in Vietnam and Their Inhibitory Effects against Enzyme Soluble Epoxide Hydrolase (sEH)

Abstract

!In the search for bioactive constituents from Vietnam medicinal plants, the leaves and stems of Murraya paniculata collected in HoaBinh Province, Vietnam were selected for chemical investigation. From the n-hexane fraction, two sterols, including β-sitosterol (6) and stigmasterol (7), and from the chloroform fraction, five coumarins, including mexoticin (1), omphalocarpin (2), murrangatin (3), kimcuongin (4), and murracarpin (5), were obtained. The structures of the isolated compounds were determined from ESI-MS, HR-ESI-MS, and NMR (1D and 2D) spectroscopic data. Coumarins (1-5) were elucidated for inhibitory effects against soluble epoxide hydrolase. Among them, coumarins (2-4) showed soluble epoxide hydrolase inhibitory activity with IC 50 values 2.2 ± 4.7, 13.9 ± 6.5, and 3.2 ± 4.5 µM, respectively. A kinetic study of the five coumarins revealed the noncompetitive enzymatic mode for 3 and 4, and a mixture of competitive/noncompetitive enzymatic modes for coumarin 2. Using molecular modelling, the coumarin kimcuongin (4) showed the best binding outline into active sites of human soluble epoxide hydrolase. Key wordsMurraya paniculata · Rutaceae · coumarin · kimcuongin · murracarpin · AutoDock/Vina · soluble epoxide hydrolase (sEH)12-(3-adamantan-1-yl-ureido) dodecanoic acid DHETs: dihydroxyeicosatrienoicdiols EETs:epoxyeicosatrienoic acidsMichaelis-Menten constant PHOME: 3-phenyl-cyano(6-methoxy-2-naphthalenyl)methyl ester-2-oxiraneacetic acid PLIP:protein-ligand interaction profiler sEH:soluble epoxide hydrolaseSupporting information available online at http://www.thieme-connect.de/productsThe sEH is the main enzyme that catalyzes the metabolism of EETs into the more polar and usually less potent metabolites DHETs [1]. Early studies have indicated that chemical compounds that can inhibit the sEHsʼ activity and stabilize the endogenous EET levels may represent potential therapeutic agents for cardiovascular disease [2,3] and the onset of several other diseases [4,5]. Murraya paniculata (L.) Jack (Rutaceae), local name "Nguyet que", is mostly grown as ornaments for its glossy green foliage and white fragrant flowers. It is used as a medicinal plant in Vietnamese traditional medicine. There were several publications of phytochemical studies of Murraya (see Supporting Information). In this study, we describe the inhibitory activity against the sEH of coumarins isolated from this plant and explain this effect by molecular modelling. The methanol extract of the dry leaves of M. paniculata was suspended with water and subsequently fractioned with n-hexane, chloroform, and ethyl acetate. From the n-hexane fraction, two sterols, β-sitosterol (6) and β-stigmasterol (7), were isolated. From the chloroform fraction of the leaves of M. paniculata, five coumarins (1-5) were subsequently isolated through column chromatography including mexoticin (1) [6], omphalocarpin (2) [7], murrangatin (3) [8], kimcuongin (4), and (−)-murracarpin (5; l " Fig. 1). The latter two coumarins are reported to possess vasorelaxing acti...

Coumarin and Moracin Derivatives from Mulberry Leaves (Morus alba L.) with Soluble Epoxide Hydrolase Inhibitory Activity

“…Molecular docking simulation indicated that sEH may interact with compound 2, 4, and 5 by forming several hydrogen bonds and hydrophobic interactions ( Figure 4 and Table 2 ). The pharmacophore analysis suggested that compound 2 created a hydrophobic interaction and a hydrogen bond with the two amino acids Asp335 and Trp466 [ 7 ], respectively, among the sEH catalytic triads (Asp335, Tyr383, and Trp466), and a strong π-π interaction with Trp336, such like 3-phenylglutaric acid [ 24 , 25 ]. While compound 4 and 5 seem to block the catalytic pocket of sEH by the interaction of A ring with all catalytic triads and C ring with Ser407, Leu408, Ser415, Leu417, and Met419, locating on the opposite side of Trp336.…”

“…Moreover, the distinctive and adaptable oxygen containing heterocyclic structure declared such an importance scaffold in coumarin compounds upon medicinal chemistry [ 6 ]. In the past decades, numerous derivatives of coumarins have been used as anticoagulant agents due to their resemblance to Vitamin K. In addition, coumarin analogues have been reported as inhibitors of sEH in previously reported literature [ 7 ], as well as many other inhibitor agents. The root bark, stem bark, and leaves of Morus alba , M. lhou , Morus macroura are the main sources for aryl-benzofuran derivatives, including the moracins.…”

Inhibitory Activity of Natural cis-Khellactone on Soluble Epoxide Hydrolase and Proinflammatory Cytokine Production in Lipopolysaccharides-Stimulated RAW264.7 Cells

“…Recent studies on sEH inhibitors have demonstrated that flavonoids [33] and sesquiterpenes [34] from natural plants exhibit significant efficacy. Specifically, coumarin derivatives, such as omphalocarpin, murrangatin, and kimcuongin from Murraya paniculata in Vietnam, have shown sEH inhibitory effects [35].…”