Design, synthesis, and biological evaluation of prenylated chalcones as 5-LOX inhibitors

Bioorg Med Chem. 2010 Aug 15;18(16):5807-15. doi: 10.1016/j.bmc.2010.06.107. Epub 2010 Jul 6.

Abstract

Ten novel mono- and di-O-prenylated chalcone derivatives were designed on the basis of a homology derived molecular model of 5-lipoxygenase (5-LOX). The compounds were docked into 5-LOX active site and the binding characteristics were quantified using LUDI. To verify our theoretical assumption, the molecules were synthesized and tested for their 5-LOX inhibitory activities. The synthesis was carried out by Claisen-Schmidt condensation reaction of mono- and di-O-prenylated acetophenones with appropriate aldehydes. 5-LOX in vitro inhibition assay showed higher potency of di-O-prenylated chalcones than their mono-O-prenylated chalcone analogs. Compound 5e exhibited good inhibition with an IC(50) at 4 microM. The overall trend for the binding energies calculated and LUDI score was in good qualitative agreement with the experimental data. Further, the compound 5e showed potent anti-proliferative effects (GI(50) at 9 microM) on breast cancer cell line, MCF-7.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arachidonate 5-Lipoxygenase / chemistry
  • Arachidonate 5-Lipoxygenase / metabolism*
  • Breast Neoplasms / drug therapy
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Chalcones / chemical synthesis
  • Chalcones / chemistry*
  • Chalcones / pharmacology*
  • Colonic Neoplasms / drug therapy
  • Humans
  • Lipoxygenase Inhibitors / chemical synthesis
  • Lipoxygenase Inhibitors / chemistry*
  • Lipoxygenase Inhibitors / pharmacology*
  • Models, Molecular
  • Structure-Activity Relationship

Substances

  • Chalcones
  • Lipoxygenase Inhibitors
  • Arachidonate 5-Lipoxygenase