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

作者：Abadi Ashraf H^*; Abouel Ella Dalal A; Lehmann Jochen; Tinsley Heather N; Gary Bernard D; Piazza Gary A; Abdel Fattah Mohammed A O

来源：European Journal of Medicinal Chemistry, 2010, 45(1): 90-97.

DOI：10.1016/j.ejmech.2009.09.029

• Multi-component reaction
• Growth inhibition
• Phosphodiesterase inhibition

Two series with the general formula of 4,6-diaryl-2-oxo-1,2 dihydropyridine-3-carbonitriles and their isosteric 4,6-diaryi-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 IC(50) value of 1.25 mu M. 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.

• 出版日期2010-1