The structure-activity relationship between oxycoumarin derivatives showing inhibitory effects on iNOS in mouse macrophage RAW264.7 cells.
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.
Nakamura
Tomonori
T
Department of Molecular Pharmacology and Pharmacotherapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675, Japan. chitoku@faculty.chiba-u.jp
Kodama
Naoko
N
Oda
Manabu
M
Tsuchiya
Shizuko
S
Arai
Yu
Y
Kumamoto
Takuya
T
Ishikawa
Tsutomu
T
Ueno
Koichi
K
Yano
Shingo
S
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
D003374:Coumarins; D008070:Lipopolysaccharides; D009569:Nitric Oxide; C030123:coumarin; D052247:Nitric Oxide Synthase Type II; C037446:5,7-dimethoxycoumarin