Inhibition of the Transcription Factor NF-κB by Sesquiterpene Lactones from Podachaenium eminens1

Abstract

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 Sls were studied for their anti-inflammatory activity using the transcription factor NF-κB as a molecular target. NF-κB is involved in the synthesis of inflammatory mediators, such as cytokines and chemokines. Except for podachaenin, all compounds completely inhibited NF-κB DNA binding in an electrophoretic mobility shift assay at concentrations between 5 and 200 μM without showing any cytotoxic effects. 3,4-Epoxydehydroleucodin possessing an α-methylene-γ-butyrolactone and a second reactive structure element by its epoxy ring α,β to a carbonyl group was most active. Although the majority of the Sls tested in this study were monofunctional only low concentrations of 50 μM were often needed for complete inhibition. Possible reasons are discussed for this result.

Abbreviations

BSA:bovine serum albuminc.p.m.:counts per minuteDTT:dithiothreitolEDTA:ethylenediaminetetraacetic acidEGTA:ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acidFCS:fetal calf serumHEPES:N-[2-hydroxyethyl]piperazine-N′-[2-ethanesul-fonic acid]NP-40:nonylphenoxypolyethoxyethanolPBS:phosphate buffered salinePMSF:phenylmethanesulfonyl fluoridePoly (dI-dC):polydeoxyinosinicdeoxycytidylic acid, double-stranded alternating copolymer

Podachaenium eminens - Asteraceae - sesquiterpene lactones - anti-inflammatory activity - NF-κB

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