Anti-inflammatory activities of hypocretenolides from Leontodon hispidus

Hypocretenolides, a small group of sesquiterpene lactones with an unusual r ing structure, are constituents of a small number of species from the Lactu ceae tribe Asteraceae). Three biogenetically closely related 14-hypocreteno lides from Leontodon hispidus L. were investigated for a putative anti-infl ammatory activity. 14-Hydroxyhypocretenolide-beta-D-glucoside-4'-14"-hydrox yhypocretenoate significantly exhibited in vivo anti-inflammatory activity in the croton oil-induced mouse ear edema. To obtain first information rega rding the molecular targets which might be affected by this constituent, tw o in vitro bioassays were performed: (ij DNA binding activity of the transc ription factor NF-kappa B was evaluated by electrophoretic mobility shift a ssay (EMSA) using TNF-alpha-activated Jurkat T cells and (ii) nitrite accum ulation in cell culture supernatants of LPS-activated RAW 264.7 macrophages was determined as a parameter for inducible nitric oxide synthase (iNOS)-d ependent nitric oxide release. In order to gain information about structure -activity relationships, additionally the aglycone 14-hydroxy-hypocretenoli de and its D-glycoside were investigated in these in vitro systems. 14-Hydr oxyhypocretenolide-beta-D-glucoside-4'-4"-hydroxyhypocretenoate as well as its aglycone exhibited activity in both test systems, whereas the D-glucosi de was not or only weakly active.