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

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-carbonitrile (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.

Figure 1

Various 3-cyano-2-oxopyridine derivatives with potential growth inhibitory and/or antiangiogenic actions through PIM-1 kinase inhibition (compound 1), survivin inhibition (compound 2) or PDE3 inhibition (compound 3).

Figure 2

Docking of PDE3A with compound (Id) in 2D diagram (a), and a MEP on a Gaussian contact surface of the binding pocket (b).

Figure 3

Molecular electrostatic potential on a Connolly surface of compound (Id) (a); amrinone (b); and compound (Ii) (c). A comparable electrostatic distribution of compound (Id) and amrinone is shown. Red is negative and blue is positive.

Figure 4

Docking of PIM-1 kinase with compound (Ii) in 2D diagram (a) and overlay of the reference compound 1 (green) and Ii (red) in the binding pocket of PIM1 kinase (b).

Scheme 1

For Ar see Table 1 and Experimental.

Scheme 2

For Ar see Table 1 and Experimental.