A SAR study on a series of synthetic lipophilic chalcones as inhibitor of transcription factor NF-κB.
To define the structural features responsible for the activity of 2,4-dihydroxy-6-isopentyloxychalcone, a newly established inhibitor of LPS induced NF-κB activation (IC(50) = 10 μM), a series of its analogues was prepared and studied for their in vitro activities against LPS induced NF-κB inhibition in RAW 264.7 cells. Among the synthesized derivatives, (E)-1-(2-(decyloxy)-6-hydroxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one (IC(50) = 2.7 μM) and (E)-1-(2-hydroxy-6-(tetradecyloxy)phenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one (IC(50) = 4.2 μM) showed the most potent inhibition. The SAR studies confirmed that the length (C(8)-C(14)) and C-6 position of linear alkyl chain of ring A is an important factor for the inhibitory activity. Hydroxyl group and its location at 4-position on ring B is also important for the inhibition. The α,β-unsaturated ketone moiety appears as a crucial motif of chalcones for the activity.
College of Pharmacy and Institute of Drug Research and Development, Chungnam, National University, Daejeon 305-764, Republic of Korea.
Eeda
E
Venkateswararao
Vinay K
VK
Sharma
Ki-Cheul
KC
Lee
Niti
N
Sharma
Sun-Hong
SH
Park
Youngsoo
Y
Kim
Sang-Hun
SH
Jung
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002599:Chalcone / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D015195:Drug Design; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D008070:Lipopolysaccharides; D016328:NF-kappa B; D002599:Chalcone; D000469:Alkaline Phosphatase