title: The structure-activity relationship between oxycoumarin derivatives showing inhibitory effects on iNOS in mouse macrophage RAW264.7 cells.
abstract: We have investigated the structure-activity relationship between 63 natural oxycoumarin derivatives and their effects on the expression of inducible-nitric oxide synthase (iNOS) induced by lipopolysaccharide. The protein expression of iNOS was screened by Western blot analysis, and four 5,7-dimethoxycoumarins were selected as potent inhibitors of iNOS expression. In terms of structural specificity, the methoxyl group on C-5 and C-7 and the short alkyl chain (1-5 carbons) on C-6 may be essential for the potent activities. These compounds also showed inhibitory effects on nitric oxide generation and mRNA expression of inflammatory mediators, namely, iNOS and COX-2. Interestingly, the inhibitory effect on mRNA expression was specific for iNOS and was not detected for neuronal NOS. It is expected that these compounds will show anti-inflammatory activities via inhibition of the expressions of iNOS and COX-2.
authors.affiliation: Department of Molecular Pharmacology and Pharmacotherapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675, Japan. chitoku@faculty.chiba-u.jp
authors.forename: Tomonori
authors.initials: T
authors.lastname: Nakamura
authors.forename: Naoko
authors.initials: N
authors.lastname: Kodama
authors.forename: Manabu
authors.initials: M
authors.lastname: Oda
authors.forename: Shizuko
authors.initials: S
authors.lastname: Tsuchiya
authors.forename: Yu
authors.initials: Y
authors.lastname: Arai
authors.forename: Takuya
authors.initials: T
authors.lastname: Kumamoto
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Koichi
authors.initials: K
authors.lastname: Ueno
authors.forename: Shingo
authors.initials: S
authors.lastname: Yano
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D015394:Molecular Structure; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013329:Structure-Activity Relationship
chemical_list: D003374:Coumarins; D008070:Lipopolysaccharides; D009569:Nitric Oxide; C030123:coumarin; D052247:Nitric Oxide Synthase Type II; C037446:5,7-dimethoxycoumarin