Activation of NF[kappa]B 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, CNathaniel, Bobrovnikova-Marjon, Ekaterina V, Abcouwer, Steve F, Royer, Robert E, Deck, Lorraine M, Jagt, David LVander
• Format: Journal Article
• Language: English
• Published: 01.04.2006
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2005.11.035

The transcription factor NFkappaB (NF[kappa]B) 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 NF[kappa]B. Enone analogues of curcumin were compared with curcumin for their abilities to inhibit the TNF alpha -induced activation of NF[kappa]B, using the Panomics' NF[kappa]B 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 NF[kappa]B 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, IC sub(50) = 3.4 +/- 0.2 mu M. 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 NF[kappa]B 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 NF[kappa]B result from the inhibition of specific targets rather than from activity as anti-oxidants.