Structure-activity relationship studies of chalcone leading to 3-hydroxy-4,3',4',5'-tetramethoxychalcone and its analogues as potent nuclear factor kappaB inhibitors and their anticancer activities

J Med Chem. 2009 Nov 26;52(22):7228-35. doi: 10.1021/jm901278z.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Transformation, Neoplastic
  • Chalcone / analogs & derivatives
  • Chalcone / chemistry*
  • Chalcone / pharmacology*
  • Chalcone / therapeutic use
  • Chalcones / chemistry*
  • Chalcones / pharmacology*
  • Chalcones / therapeutic use
  • Female
  • Genes, Reporter
  • Humans
  • I-kappa B Kinase / antagonists & inhibitors
  • Inhibitory Concentration 50
  • Interleukin-1 Receptor-Associated Kinases / antagonists & inhibitors
  • Luciferases / metabolism
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Nude
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Structure-Activity Relationship
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • 3-hydroxy-4,3',4',5'-tetramethoxychalcone
  • Antineoplastic Agents
  • Chalcones
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Chalcone
  • Luciferases
  • Interleukin-1 Receptor-Associated Kinases
  • I-kappa B Kinase