Stereospecific inhibition of nitric oxide production in macrophage cells by flavanonols: Synthesis and the structure-activity relationship.
To explore the structure-activity relationships on the inhibitory activity of flavanonols against nitric oxide (NO) production in inflammatory cells, we synthesized 19 flavanonols which shared a common 3,5,7-trihydroxychroman scaffold. A range of substitutions was included in the B ring in order to investigate the structure-activity relationship. We also succeeded in isolating stereoisomers from 16 of the flavanonols using chiral column chromatography. The inhibitory effects of these compounds on NO production were examined in RAW 264.7 cells (a murine macrophage-like cell line), which were activated by lipopolysaccharide (LPS). We only observed inhibitory activity against NO production in (2R,3R) stereoisomers, while the inhibitory activities of (2S,3S) stereoisomers were significantly weaker. We also evaluated the free radical scavenging potential of the flavanonols using 1,1-diphenyl-2-picrylhydrazyl (DPPH). Each stereoisomer indicated the equivalent DPPH scavenging potential as expected. The radical scavenging activity was not correlated with the inhibitory activity against NO. The inhibition of NO production by flavanonols is stereospecific and cannot simply be explained by their radical scavenging activity. We propose the possible existence of a 'target' molecule for flavanonols which is involved in the production and/or regulation of NO in RAW 264.7 cells.
School of Pharmacy, Nihon University, 7-7-1 Narashino-dai, Funabashi-shi, Chiba 274-8555, Japan.
Wen-Jun
WJ
Jiang
School of Pharmacy, Nihon University, 7-7-1 Narashino-dai, Funabashi-shi, Chiba 274-8555, Japan; Department of Pharmacognosy, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya-shi, Aichi 467-8603, Japan.
Kan'ichiro
K
Ishiuchi
School of Pharmacy, Nihon University, 7-7-1 Narashino-dai, Funabashi-shi, Chiba 274-8555, Japan.
Megumi
M
Furukawa
School of Pharmacy, Nihon University, 7-7-1 Narashino-dai, Funabashi-shi, Chiba 274-8555, Japan.
Tomoko
T
Takamiya
School of Pharmacy, Nihon University, 7-7-1 Narashino-dai, Funabashi-shi, Chiba 274-8555, Japan.
Susumu
S
Kitanaka
School of Pharmacy, Nihon University, 7-7-1 Narashino-dai, Funabashi-shi, Chiba 274-8555, Japan. Electronic address: iijima.hiroshi@nihon-u.ac.jp.
Hiroshi
H
Iijima
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D002839:Chromans; D016166:Free Radical Scavengers; D008070:Lipopolysaccharides; D009569:Nitric Oxide
Anti-oxidation; Flavonoid; Nitric oxide; Stereoisomer; Synthesis