Design, synthesis and biological evaluation of novel pyridine derivatives as anticancer agents and phosphodiesterase 3 inhibitors.

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Abadi AH, Ibrahim TM, Abouzid KM, Lehmann J, Tinsley HN, Gary BD, Piazza GA

Design, synthesis and biological evaluation of novel pyridine derivatives as anticancer agents and phosphodiesterase 3 inhibitors.

Bioorg Med Chem. 2009 Aug 15;17(16):5974-82. doi: 10.1016/j.bmc.2009.06.063. Epub 2009 Jul 3.

PubMed ID

19628397 [ View in PubMed

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Abstract

Two series of 4,6-diaryl-2-imino-1,2-dihydropyridine-3-carbonitriles and their isosteric 4,6-diaryl-2-oxo-1,2-dihydropyridine-3-carbonitriles were synthesized through a combinatorial approach. The prepared analogues were evaluated for their in vitro capacity to inhibit PDE3A and the growth of the human HT-29 colon adenocarcinoma tumor cell line. Compound 6-(4-bromophenyl)-4-(2-ethoxyphenyl)-2-imino-1,2-dihydropyridine-3-carbonitrile (Id) exhibited the strongest PDE3 inhibition when cGMP but not cAMP is the substrate with a IC(50)of 27microM, which indicates a highly selective mechanism of enzyme inhibition. On the other hand, compound 6-(1,3-benzodioxol-5-yl)-4-(2-ethoxyphenyl)-2-imino-1,2-dihydropyridine-3-carboni trile (Ii) was the most active in inhibiting colon tumor cell growth with a IC(50) of 3microM. The electronic effects, steric effects and conformational aspects of Id seem to be the most crucial for the PDE3 inhibition. Meanwhile, steric factors and the H-bonding capability seem to be the most important factors for tumor cell growth inhibitory activity. Conversely, there is no direct correlation between PDE3 inhibition and anticancer activity for the prepared compounds. An in silico docking experiment indicates the potential involvement of other potential molecular targets such as PIM-1 kinase to explain its tumor cell growth inhibitory activity.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Milrinone	cGMP-inhibited 3',5'-cyclic phosphodiesterase A	IC 50 (nM)	11400	N/A	N/A	Details
Milrinone	cGMP-inhibited 3',5'-cyclic phosphodiesterase A	IC 50 (nM)	3600	N/A	N/A	Details