Oxacyclododecindione, a Novel Inhibitor of IL-4 Signaling from Exserohilum rostratum

Abstract

In a screening program for new metabolites from fungi inhibiting the IL-4 mediated signal transduction, a novel chlorinated macrocyclic lactone, designated as oxacyclododecindione, was isolated from fermentations of the imperfect fungus Exserohilum rostratum. The structure was determined by a combination of spectroscopic techniques. Oxacyclododecindione inhibits the IL-4 induced expression of the reporter gene secreted alkaline phosphatase (SEAP) in transiently transfected HepG2 cells with IC 50 values of 20ϳ25 ng/ml (54ϳ67.5 nM). Studies on the mode of action of the compound revealed that the inhibition of the IL-4 dependent signaling pathway is caused by blocking the binding of the activated STAT6 transcription factors to the DNA binding site without inhibiting tyrosine phosphorylation. The compound has no antibacterial or antifungal activity.

Total synthesis of two potent anti-inflammatory macrolactones of the oxacyclododecindione type

“…2,22 The biological activities of the synthetic derivatives in comparison with those of the natural occurring compounds 14-deoxycyclododecindione and 10,11-dehydrocurvularin are shown in Table 1. To exclude unspecific cytotoxic effects, the results were normalized against the constitutive active EF1α-promoter in front of the luciferase gene in order as described previously.…”

“…2 The STAT6 expression plasmid (TOPO-Stat6) has been previously described. The STAT6-driven reporter plasmid pGL3-TK-7xN 4 contains the herpes simplex virus thymidine kinase promoter under the control of 7 copies of the palindromic sequence TTC(N) 4 GAA.…”

The fungal secondary metabolite trichodimerol inhibits TGF-β dependent cellular effects and tube formation of MDA-MB-231 cells

“…The influence of trichodimerol on the synthesis of macromolecules in HepG2 cells was analyzed by determining the incorporation of [2-14 C]thymidine, [2-14 C]uridine or [1-14 C] leucine in trichloroacetic acid (TCA) insoluble fractions as described recently [16].…”

Inhibition of TGF-β signaling, vasculogenic mimicry and proinflammatory gene expression by isoxanthohumol

“…The influence of isoxanthohumol on the synthesis of macromolecules in HepG2 cells was analyzed by determining the incorporation of [2-14 C] thymidine, [2-14 C]uridine or [1-14 C]leucine in trichloroacetic acid (TCA) insoluble fractions as described recently [21].…”