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

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 malon...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2010-01, Vol.45 (1), p.90-97
Main Authors: Abadi, Ashraf H., Abouel-Ella, Dalal A., Lehmann, Jochen, Tinsley, Heather N., Gary, Bernard D., Piazza, Gary A., Abdel-Fattah, Mohammed A.O.
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Biological and medical sciences
Cell Proliferation - drug effects
Colonic Neoplasms - pathology
Combinatorial Chemistry Techniques
Cyclic Nucleotide Phosphodiesterases, Type 3
Drug Discovery
General aspects
Growth inhibition
HT29 Cells
Humans
Inhibitory Concentration 50
Isoenzymes - antagonists & inhibitors
Medical sciences
Models, Molecular
Molecular Conformation
Multi-component reaction
Pharmacology. Drug treatments
Phosphodiesterase 3 Inhibitors
Phosphodiesterase inhibition
Pyridones - chemistry
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Summary: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 IC 50 value of 1.25 μM. 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. [Display omitted]
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2009.09.029