Studies on the antioxidative activity of phloroglucinol derivatives isolated from hypericum species.
Twenty-one phloroglucinol derivatives, belonging to 8 different carbon skeletons, were tested for their ability to influence the oxidative burst of polymorphonuclear cells (PMNs) after stimulation with N-formyl-methionyl-leucyl-phenylalanine (FMLP) or opsonized zymosan (OZ). Results revealed a strong reduction of oxygen production by PMNs after stimulation with FMLP for the compounds ialibinone E ( 5), hyperguinone B ( 15) and hyperforin ( 21). The IC 50 values obtained were 2.5 microM ( 5), 3.3 microM ( 15) and 1.8 microM ( 21), respectively. Slight modifications of the substituents or variation of the stereochemistry resulted in a significant loss of activity. None of the active compounds showed antioxidative activity after stimulation with OZ. The influence of compounds 5, 15 and 21 on the production of oxygen radicals in an H 2 O 2 /horseradish peroxidase system was investigated and revealed potent activity only for compound 5 (IC 50 1 microM). The superoxide-scavenging properties of ialibinone E ( 5) and hyperguinone B ( 15) were additionally tested in a cytochrome c assay and only ialibinone E ( 5) was found to be significantly active at lower micromolar concentrations. Ialibinone E ( 5) was not active in a xanthine oxidase assay (urate formation) in concentrations up to 100 microM and its activity is therefore not attributable to the inhibition of this enzyme. It can be assumed that the activity of compounds 5 and 15 in the different cellular and enzymatic assays, is most likely caused by different and maybe specific mechanisms and cannot be explained by a radical scavenger activity alone. None of the active phloroglucinols showed cytotoxic effects against the PMNs.
Heilmann
J
J
Department of Applied BioSciences, Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Zürich. joerg.heilmann@pharma.anbi.ethz.ch
Winkelmann
K
K
Sticher
O
O
D000975:Antioxidants / Q000494:pharmacology*; D006801:Humans; D020902:Hypericum; D008163:Luminescent Measurements; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects*; D010696:Phloroglucinol / Q000031:analogs & derivatives / Q000494:pharmacology*; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016897:Respiratory Burst / Q000187:drug effects
D000975:Antioxidants; D010936:Plant Extracts; D017382:Reactive Oxygen Species; D010696:Phloroglucinol