Inhibitory effects of sesquiterpenes from Saussurea lappa on the overproduction of nitric oxide and TNF-alpha release in LPS-activated macrophages.
Nitric oxide (NO), derived from L-arginine, is produced by two types (constitutive and inducible) of nitric oxide synthase (NOS: cNOS and iNOS). The NO produced in large amounts by the iNOS is known to be responsible for inflammation, the vasodilation, and hypotension observed in septic shock and cancer metastasis. The inhibitors of the overproduction of NO, thus, may be useful candidates for the treatment of inflammatory diseases. We have found that the petroleum ether extract of Saussurea lappa Decne, which is a wild species wildly distributed in India, can strongly inhibit the overproduction of NO in mouse macrophage RAW 264.7 cells. Through bioassay-guided fractionation, 13 sesquiterpenes were isolated from the active petroleum ether extract. Furthermore, another five sesquiterpenes were synthesized by chemical methods. In the present study, their effects on LPS-induced NO production and TNF-alpha release are reported. Compounds 1, 3, 9, 17, and 18 showed significant inhibitory activities on the production of NO and release of TNF-alpha with IC(50) values lower than 1 micromol/l. SAR studies suggest that the exocyclic double bond (Delta(11(13))) is necessary for the inhibitory activities of sesquiterpenes on the NO production.
Zhao
Feng
F
School of Pharmacy, Yantai University, Yantai, China.
Xu
Hui
H
He
En-Qi
EQ
Jiang
Yong-Tao
YT
Liu
Ke
K
D000818:Animals; D002460:Cell Line; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D015394:Molecular Structure; D009569:Nitric Oxide / Q000378:metabolism*; D030441:Saussurea / Q000737:chemistry*; D012717:Sesquiterpenes / Q000737:chemistry* / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D008070:Lipopolysaccharides; D012717:Sesquiterpenes; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide