2--hydroxychalcone and Cell-Transformation--Neoplastic

Chalcone is a privileged structure, demonstrating promising anti-inflammatory and anticancer activities. One potential mechanism is to suppress nuclear factor kappa B (NF-kappaB) activation. The structures of chalcone-based NF-kappaB 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-kappaB inhibition, to explore the feasibility of developing simple chalcone-based potent NF-kappaB 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-kappaB inhibitory activities, some of low micromolar potency, establishing that structural complexity is not required for NF-kappaB inhibition. Lead compounds also demonstrate potent cytotoxicity against lung cancer cells. Their cytotoxicities correlate moderately well with their NF-kappaB inhibitory activities, suggesting that suppressing NF-kappaB 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.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Chalcone; Chalcones; Female; Genes, Reporter; Humans; I-kappa B Kinase; Inhibitory Concentration 50; Interleukin-1 Receptor-Associated Kinases; Luciferases; Lung Neoplasms; Mice; Mice, Nude; NF-kappa B; Structure-Activity Relationship; Tumor Necrosis Factor-alpha