Inhibition of TNF-alpha promoter activity and synthesis by A11-99-1, a new cyclopentenone from the ascomycete Mollisia melaleuca.
In a search for inhibitors of the inducible tumor necrosis factor-a (TNF-a) promoter activity and synthesis, a new chlorinated cyclopentenone was isolated from fermentations of the ascomycete Mollisia melaleuca. The structure was determined by a combination of spectroscopic techniques The compound blocked the inducible human TNF-alpha promoter activity and synthesis with IC50-values of 2.5-5 microg/ml (8.1-16.1 microM). Studies on the mode of action of the compound revealed that the inhibition of TNF-a promoter activity is caused by an inhibition of the phosphorylation of the IkappaB protein which prevents the activation of the transcription factor NF-xB. No cytotoxic, antibacterial and antifungal activities could be observed up to 100 microg/ml (323 microM) of the compound.
Rether
Jan
J
Institut für Biotechnologie und Wrikstoff-Forschung, Kaiserslautern, Germany.
Erkel
Gerhard
G
Sterner
Olov
O
Anke
Timm
T
D001203:Ascomycota / Q000737:chemistry*; D003517:Cyclopentanes / Q000494:pharmacology*; D005285:Fermentation; D007700:Kinetics; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
C504596:3-chloro-4-dichloromethyl-5-dichloromethylene-2,4-dihydroxycyclopent-2-enone; D003517:Cyclopentanes; D014409:Tumor Necrosis Factor-alpha; C013905:cyclopentenone