Activation of NFkappaB is inhibited by curcumin and related enones

• Published in: Bioorganic & medicinal chemistry Vol. 14; no. 7; pp. 2450 - 2461
• Main Authors: Weber, Waylon M, Hunsaker, Lucy A, Roybal, C Nathaniel, Bobrovnikova-Marjon, Ekaterina V, Abcouwer, Steve F, Royer, Robert E, Deck, Lorraine M, Vander Jagt, David L
• Format: Journal Article
• Language: English
• Published: England 01.04.2006
• Subjects: Cell Line; Cell Survival - drug effects; Curcumin - chemical synthesis; Curcumin - chemistry; Curcumin - pharmacology; Dose-Response Relationship, Drug; Enzyme Activation - drug effects; Humans; Hydrogen Bonding; Ketones - chemical synthesis; Ketones - chemistry; Ketones - pharmacology; Molecular Structure; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; Quantitative Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391

The transcription factor NFkappaB (NFkappaB) is up-regulated in many cancer cells where it contributes to development of the pro-survival, anti-apoptotic state. The natural product curcumin is a known inhibitor of activation of NFkappaB. Enone analogues of curcumin were compared with curcumin for their abilities to inhibit the TNFalpha-induced activation of NFkappaB, using the Panomics' NFkappaB Reporter Stable Cell Line. The enones tested included curcumin analogues that retained the 7-carbon spacer between the aromatic rings, analogues with a 5-carbon spacer, and analogues with a 3-carbon spacer. Inhibitors of NFkappaB activation were identified in all three series, a number of which were more active than curcumin. Enone analogues in the series with the 5-carbon spacer were especially active, including members that contained heterocyclic rings. 1,5-Bis(3-pyridyl)-1,4-pentadien-3-one was the most active analogue, IC50 = 3.4 +/- 0.2 microM. The most active analogues retain the enone functionality, although some analogues devoid of the enone functionality exhibited activity. The activity of the analogues as inhibitors of the activation of NFkappaB did not correlate with their anti-oxidant activity. The data suggest that the abilities of curcumin and analogues to prevent the stress-induced activation of NFkappaB result from the inhibition of specific targets rather than from activity as anti-oxidants.