Abstract
Recently, dibenzylurea-based potent soluble epoxide hydrolase (sEH) inhibitors were identified in Pentadiplandra brazzeana, a plant in the order Brassicales. In an effort to generalize the concept, we hypothesized that plants that produce benzyl glucosinolates and corresponding isothiocyanates also produce these dibenzylurea derivatives. Our overall aim here was to examine the occurrence of urea derivatives in Brassicales, hoping to find biologically active urea derivatives from plants. First, plants in the order Brassicales were analyzed for the presence of 1, 3-dibenzylurea (compound 1), showing that three additional plants in the order Brassicales produce the urea derivatives. Based on the hypothesis, three dibenzylurea derivatives with sEH inhibitory activity were isolated from maca (Lepidium meyenii) roots. Topical application of one of the identified compounds (compound 3, human sEH IC50 = 222 nM) effectively reduced pain in rat inflammatory pain model, and this compound was bioavailable after oral administration in mice. The biosynthetic pathway of these urea derivatives was investigated using papaya (Carica papaya) seed as a model system. Finally, a small collection of plants from the Brassicales order was grown, collected, extracted and screened for sEH inhibitory activity. Results show that several plants of the Brassicales order could be potential sources of urea-based sEH inhibitors.
Highlights
Soluble epoxide hydrolase is the major enzyme responsible for the hydrolysis of epoxy fatty acids to their corresponding diols in humans and other mammals [1]
Tsopmo et al reported 1, 3-dibenzylurea derivatives in the root of a plant in Cameroon, Pentadiplandra brazzeana, and we recently reported these urea derivatives as potent soluble epoxide hydrolase (sEH) inhibitors [17,18]
We looked for 1, 3-dibenzylurea in plants in the order Brassicales that have been reported to produce benzyl glucosinolate or benzyl isothiocyanate
Summary
Soluble epoxide hydrolase (sEH, EC 3.3.2.10) is the major enzyme responsible for the hydrolysis of epoxy fatty acids to their corresponding diols in humans and other mammals [1]. These epoxy fatty acids are pleiotropic endogenous mediators with key functions in inflammation, pain and blood pressure regulation [1,2,3]. Increasing the levels of endogenous epoxy fatty acids by inhibiting sEH has been shown to block and resolve inflammation, reduce pain and lower blood pressure in numerous in vivo animal models [2,4,5,6,7,8,9]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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