Mode of action and target identification of anti-inflammatory natural products

In the present thesis, the mode of action of three different natural secondary metabolites was clarified in human cancer cells and primary immune cells. The investigated compounds of this work were (I) the mycotoxin gliotoxin from Aspergillus fumigatus targeting leukotriene A4 hydrolase (LTA4H) resulting in a reduction of the biosynthesis of the neutrophil chemoattractant leukotriene B4 (LTB4) in vivo and in vitro. Furthermore, gliotoxin caused a reduced neutrophil infiltration into the peritoneal cavity. Interestingly, gliotoxin suppressed solely LTB4 formation without compromising other eicosanoids identifying thereby the cause of neutropenia during invasive aspergillosis (IA). However, gliotoxin failed to impede LTA4H activity in non-cellular systems but pre-incubation with GSH enables inhibition of LTA4H activity by gliotoxin indicating that reducing conditions were crucial to cleave the intramolecular disulfide bond. The formed free thiol groups chelated the zinc ion in the active epoxide hydrolase center of LTA4H. Second (II), the melleolide dehydroarmillylorsellinate (DAO) exhibiting, on the one hand, anti-inflammatory features by abrogating 5-lipoxygenase (5-LOX) product formation due to an interaction with surface cysteines especially C159 located at the entrance to the active center of 5-LOX hampering the interaction between 5-LOX and the 5-LOX activating protein (FLAP), and on the other hand, manipulate monocyte functions by covalent binding of the cellular membrane constituent phosphatidylethanolamine (PE). And finally (III), myxochelin A biosynthesized by Pyxidicoccus fallax hampering 5-LOX activity due to iron chelation by the catechol basic structure. Over the last decades, the link between inflammation and cancer gains relevance. Hence, it is important to investigate new anti-inflammatory drugs to prevent chronic diseases, and to elucidate the mechanism of action of cytotoxic compounds to develop new strategies of action for anti-cancer drugs.



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