TY - JOUR
T1 - Structure - Activity relationship studies of chalcone leading to 3-hydroxy-4,3′,4′,5′-tetramethoxychalcone and its analogues as potent nuclear factor κB inhibitors and their anticancer activities
AU - Srinivasan, Balasubramanian
AU - Johnson, Thomas E.
AU - Lad, Rahul
AU - Xing, Chengguo
PY - 2009/11/26
Y1 - 2009/11/26
N2 - Chalcone is a privileged structure, demonstrating promising anti-inflammatory and anticancer activities. One potential mechanism is to suppress nuclear factor kappa B (NF-κB) activation. The structures of chalcone-based NF-κB inhibitors vary significantly that there is minimum information about their structure-activity relationships (SAR). This study aims to establish SAR of chalcone-based compounds to NF-κB inhibition, to explore the feasibility of developing simple chalcone-based potent NF-κB inhibitors, and to evaluate their anticancer activities. Three series of chalcones were synthesized in one to three steps with the key step being aldol condensation. These candidates demonstrated a wide range of NF-κB inhibitory activities, some of low micromolar potency, establishing that structural complexity is not required for NF-κB inhibition. Lead compounds also demonstrate potent cytotoxicity against lung cancer cells. Their cytotoxicities correlate moderately well with their NF-κB inhibitory activities, suggesting that suppressing NF-κB activation is likely responsible for at least some of the cytotoxicities. One lead compound effectively inhibits lung tumor growth with no signs of adverse side effects.
AB - Chalcone is a privileged structure, demonstrating promising anti-inflammatory and anticancer activities. One potential mechanism is to suppress nuclear factor kappa B (NF-κB) activation. The structures of chalcone-based NF-κB inhibitors vary significantly that there is minimum information about their structure-activity relationships (SAR). This study aims to establish SAR of chalcone-based compounds to NF-κB inhibition, to explore the feasibility of developing simple chalcone-based potent NF-κB inhibitors, and to evaluate their anticancer activities. Three series of chalcones were synthesized in one to three steps with the key step being aldol condensation. These candidates demonstrated a wide range of NF-κB inhibitory activities, some of low micromolar potency, establishing that structural complexity is not required for NF-κB inhibition. Lead compounds also demonstrate potent cytotoxicity against lung cancer cells. Their cytotoxicities correlate moderately well with their NF-κB inhibitory activities, suggesting that suppressing NF-κB activation is likely responsible for at least some of the cytotoxicities. One lead compound effectively inhibits lung tumor growth with no signs of adverse side effects.
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U2 - 10.1021/jm901278z
DO - 10.1021/jm901278z
M3 - Article
C2 - 19883086
AN - SCOPUS:70949087763
SN - 0022-2623
VL - 52
SP - 7228
EP - 7235
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 22
ER -