Inhibition of the transcription factor NF-κB by sesquiterpene lactones from Podachaenium eminens

Investigation of Podachaenium eminens afforded nine sesquiterpene lactones (Sls) from which costunolide, 7-hydroxycostunolide, santamarin as well as 3-chlorodehydroleucodin are new for this plant and 3,4-dehydro-4-dehydroxypodachaenin (= 3-costoyloxydehydroleucodin) is found for the first time in nature. All isolated Sis were studied for their anti-inflammatory activity using the transcription factor NF-kappaB as a molecular target. NF-kappaB is involved in the synthesis of inflammatory mediators, such as cytokines and chemokines. Except for podachaenin, all compounds completely inhibited NF-kappaB DNA binding in an electrophoretic mobility shift assay at concentrations between 5 and 200 muM without showing any cytotoxic effects. 3,4-Epoxydehydroleucodin possessing an alpha -methylene-gamma -butyrolactone and a second reactive structure element by its epoxy ring alpha,beta to a carbonyl group was most active. Although the majority of the Sis tested in this study were monofunctional only low concentrations of 50 muM were often needed for complete inhibition. Possible reasons are discussed for this result.