title: Inhibition of NO production in LPS-stimulated mouse macrophage-like cells by trihaloacetylazulene derivatives.
abstract: The effect of 20 trihaloacetylazulene derivatives with one halogen atom, on nitric oxide (NO) production by mouse macrophage-like cells Raw 264.7 was investigated. 2-Methoxyazulenes and 2-ethoxyazulenes exhibited comparable cytotoxicity. Trichloroacetylazulenes generally exhibited higher cytotoxicity, as compared with the corresponding trifluoroacetylazulenes. Substitution of chloride, bromide or iodine at the C-3 position further enhanced their cytotoxicity. All of these compounds failed to stimulate the Raw 264.7 cells to produce detectable amounts of NO, but did inhibit NO production by LPS-activated Raw 264.7 cells to different extents. 1-Trichloroacetyl-2-methoxyazulene and 1-trichloroacetyl-2-ethoxyazulene, with less cytotoxic activity, inhibited NO production to the greatest extent, producing the highest selectivity index (SI) of >24.7 and >28.7, respectively. This was accompanied by the efficient inhibition of inducible NO synthase (iNOS) mRNA expression, but not by iNOS protein abundance. Electron spin resonance (ESR) spectroscopy showed that neither of these compounds produced radicals, nor scavenged NO, superoxide anion or diphenyl-2-picrylhydrazyl radicals. The present study suggests that the inhibitory effects of trifluoroacetylazulenes and trichloroacetylazulenes on NO production by activated macrophages might be derived from the perturbation of NO anabolism (inhibition of iNOS mRNA expression and possibly the inactivation of iNOS protein) rather than NO catabolism (NO scavenging).
authors.affiliation: Faculty of Science, Josai University, Sakado, Saitama, Japan.
authors.forename: Juri
authors.initials: J
authors.lastname: Takahashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Sekine
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nishishiro
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Arai
authors.forename: Hidetsugu
authors.initials: H
authors.lastname: Wakabayashi
authors.forename: Teruo
authors.initials: T
authors.lastname: Kurihara
authors.forename: Ken
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Kazue
authors.initials: K
authors.lastname: Satoh
authors.forename: Noboru
authors.initials: N
authors.lastname: Motohashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakagami
mesh_terms: D000107:Acetylation; D000818:Animals; D052176:Azulenes / Q000494:pharmacology*; D004578:Electron Spin Resonance Spectroscopy; D016166:Free Radical Scavengers / Q000494:pharmacology; D006846:Hydrocarbons, Halogenated / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D052176:Azulenes; D016166:Free Radical Scavengers; D006846:Hydrocarbons, Halogenated; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse