Discovery of colon tumor cell growth inhibitory agents through a combinatorial approach

Eur J Med Chem. 2010 Jan;45(1):90-7. doi: 10.1016/j.ejmech.2009.09.029. Epub 2009 Sep 20.


Two series with the general formula of 4,6-diaryl-2-oxo-1,2 dihydropyridine-3-carbonitriles and their isosteric 4,6-diaryl-2-imino-1,2-dihydropyridine-3-carbonitrile were synthesized through one pot reaction of the appropriate acetophenone, aldehyde, ammonium acetate with ethyl cyanoacetate or malononitrile, respectively. The synthesized compounds were evaluated for their tumor cell growth inhibitory activity against the human HT-29 colon tumor cell line, as well as their PDE3 inhibitory activity. Compound 4-(2-Ethoxyphenyl)-2-oxo-6-thiophen-3-yl-1,2-dihydropyridine-3 carbonitrile (21) showed tumor cell growth inhibitory activity with an IC50 value of 1.25 microM. Meanwhile, 4-(4-Ethoxyphenyl)-2-imino-6-(thiophen-3-yl)-1,2-dihydropyridine-3-carbonitrile (26) showed inhibitory effect upon PDE3 using cAMP or cGMP as substrate. No correlation exists between PDE3 inhibition and the tumor cell growth inhibitory activity. Docking compound 21 to other possible molecular targets showed the potential to bind PIM1 Kinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Colonic Neoplasms / pathology*
  • Combinatorial Chemistry Techniques*
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • Drug Discovery*
  • HT29 Cells
  • Humans
  • Inhibitory Concentration 50
  • Isoenzymes / antagonists & inhibitors
  • Models, Molecular
  • Molecular Conformation
  • Phosphodiesterase 3 Inhibitors
  • Pyridones / chemistry


  • Antineoplastic Agents
  • Isoenzymes
  • Phosphodiesterase 3 Inhibitors
  • Pyridones
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • PDE3A protein, human