Inhibitory effects of sesquiterpenes from Saussurea lappa on the overproduction of nitric oxide and TNF- 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- release are reported. Compounds 1, 3, 9, 17, and 18 showed significant inhibitory activities on the production of NO and release of TNF- with IC50 values lower than 1mol/l. SAR studies suggest that the exocyclic double bond (11(13)) is necessary for the inhibitory activities of sesquiterpenes on the NO production.