Isolation, semisynthesis, covalent docking and transforming growth factor beta-activated kinase 1 (TAK1)-inhibitory activities of (5Z)-7-oxozeaenol analogues

Bioorg Med Chem. 2015 Nov 1;23(21):6993-9. doi: 10.1016/j.bmc.2015.09.037. Epub 2015 Sep 25.

Abstract

(5Z)-7-Oxozeanol and related analogues were isolated and screened to explore their activity as TAK1 inhibitors. Seven analogues were synthesized and more than a score of natural products isolated that examined the role that different areas of the molecule contribute to TAK1 inhibition. A novel nonaromatic difluoro-derivative was synthesized that had similar potency compared to the lead. This is the first example of a nonaromatic compound in this class to have TAK1 inhibition. Covalent docking for the isolated and synthesized analogues was carried out and found a strong correlation between the observed activities and the calculated binding.

Keywords: (5Z)-7-Oxozeaenol; Covalent docking; Resorcylic acid lactone; Selectfluor®; TAK1.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Binding Sites
  • Humans
  • Inhibitory Concentration 50
  • MAP Kinase Kinase Kinases / antagonists & inhibitors*
  • MAP Kinase Kinase Kinases / metabolism
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / metabolism
  • Protein Structure, Tertiary
  • Zearalenone / analogs & derivatives*
  • Zearalenone / chemical synthesis
  • Zearalenone / chemistry
  • Zearalenone / metabolism

Substances

  • 7-oxozeanol
  • Protein Kinase Inhibitors
  • Zearalenone
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7