Occurrence of urea-based soluble epoxide hydrolase inhibitors from the plants in the order Brassicales

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.

Prospective for cytochrome P450 epoxygenase cardiovascular and renal therapeutics

“…The search for therapeutics in nature that could alter epoxy-fatty acid levels has recently intensified. Plant-derived sEH inhibitors have recently been identified from Cimicifuga dahurica roots and from plants in the order Brassicales (Kitamura et al, 2017; Thao et al, 2017). These plant-derived sEH inhibitors have not been tested for favorable renal and cardiovascular actions.…”

N-Benzyl-linoleamide, a Constituent of Lepidium meyenii (Maca), Is an Orally Bioavailable Soluble Epoxide Hydrolase Inhibitor That Alleviates Inflammatory Pain

“…The addition of a meta -methoxy to the phenyl ring ( 8 – 14 ) generally decreased IC 50 values compared to unsubstituted analogues ( 1 – 7 ). This indicated that methoxy groups at meta positions can enhance sEH inhibition, as has been demonstrated with benzyl-containing urea-based natural sEH inhibitors . A second, para -methoxy ( 15 – 17 ), however, did not improve inhibitory potency.…”

“…This could be particularly important in developing countries. Previously, a number of chemicals from a variety of natural sources have been identified as sEHI, − including urea- and amide-based inhibitors from plants in the order Brassicales. , However, a large number of these compounds have a low potency or their concentrations in the plant are insufficient for clinical application.…”

Aplicações Terapêuticas Da Lepidium Meyenii (Maca) E Seus Compostos Químicos: Uma Revisão Sistemática / Therapeutic Applications of Lepidium Meyenii (Maca) and Its Chemical Compounds: A Systematic Review

“…Ações anti-inflamatórias foram citadas, Tenci et al (2017) apontaram as macamidas e metabólitos lipofílicos de extratos da maca, como possível tratamento contra a dor osteoarticular e neuropática. Para Kitamura et al (2017), o composto químico 1,3-Bis(3-metoxibenzil), demonstrou ação analgésica esperada contra a dor inflamatória induzida em ratos. Nos estudos de Almukadi et al, 2013, as macamidas atuaram no sistema nervoso central para fornecer efeitos analgésicos, antiinflamatórios ou neuroprotetores, modulando a liberação de neurotransmissores.…”