title: Inhibition of in vitro leukotriene B4 biosynthesis in human neutrophil granulocytes and docking studies of natural quinones.
abstract: Quinones are compounds frequently contained in medicinal plants used for the treatment of inflammatory diseases. Therefore, the impact of plant-derived quinones on the arachidonic acid metabolic pathway is worthy of investigation. In this study, twenty-three quinone compounds of plant origin were tested in vitro for their potential to inhibit leukotriene B4 (LTB4) biosynthesis in activated human neutrophil granulocytes with 5-lipoxygenase (5-LOX) activity. The benzoquinones primin (3) and thymohydroquinone (4) (IC50 = 4.0 and 4.1 microM, respectively) showed activity comparable with the reference inhibitor zileuton (1C50 = 4.1 microM). Moderate activity was observed for the benzoquinone thymoquinone (2) (1C50 = 18.2 microM) and the naphthoquinone shikonin (1) (IC50 = 24.3 microM). The anthraquinone emodin and the naphthoquinone plumbagin (5) displayed only weak activities (IC50 > 50 microM). The binding modes of the active compounds were further evaluated in silico by molecular docking to the human 5-LOX crystal structure. This process supports the biological data and suggested that, although the redox potential is responsible for the quinone's activity on multiple targets, in the case of 5-LOX the molecular structure plays a vital role in the inhibition. The obtained results suggest primin as a promising compound for the development of dual COX-2/5-LOX inhibitors.
authors.affiliation: Laboratory of Plant Biotechnologies, Institute of Experimental Botany AS CR, v.v.i., 165 02 Prague 6 - Lysolaje, Czech Republic. landa@ueb.cas.cz
authors.forename: Premysl
authors.initials: P
authors.lastname: Landa
authors.forename: Zsofia
authors.initials: Z
authors.lastname: Kutil
authors.forename: Veronika
authors.initials: V
authors.lastname: Temml
authors.forename: Jan
authors.initials: J
authors.lastname: Malik
authors.forename: Ladislav
authors.initials: L
authors.lastname: Kokoska
authors.forename: Ute
authors.initials: U
authors.lastname: Widowitz
authors.forename: Marie
authors.initials: M
authors.lastname: Pribylova
authors.forename: Marcela
authors.initials: M
authors.lastname: Dvorakova
authors.forename: Petr
authors.initials: P
authors.lastname: Marsik
authors.forename: Daniela
authors.initials: D
authors.lastname: Schuster
authors.forename: Rudolf
authors.initials: R
authors.lastname: Bauer
authors.forename: Tomas
authors.initials: T
authors.lastname: Vanek
mesh_terms: D000893:Anti-Inflammatory Agents / Q000032:analysis; D016227:Benzoquinones / Q000494:pharmacology; D052246:Cyclooxygenase 2 Inhibitors / Q000032:analysis; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors / Q000032:analysis*; D062105:Molecular Docking Simulation; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010936:Plant Extracts / Q000737:chemistry* / Q000494:pharmacology; D010946:Plants, Medicinal / Q000737:chemistry; D011809:Quinones / Q000494:pharmacology*; D013943:Thymol / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D016227:Benzoquinones; D052246:Cyclooxygenase 2 Inhibitors; D016859:Lipoxygenase Inhibitors; D010936:Plant Extracts; D011809:Quinones; D007975:Leukotriene B4; C003465:thymohydroquinone; D013943:Thymol; C014773:primin