Anticancer pyridines induce G2/M arrest and apoptosis via p53 and JNK upregulation in liver and breast cancer cells

Abstract

In the present study, the synthesis and biological evaluation of one novel pyridine and one novel pyridone anticancer compound is reported. The compounds 6-(2,4-dimetho xyphenyl)-4-(3,4-methylenedioxyphenyl)-1H-pyridin-2-one (1) and 2-(2,4-dimethoxyphenyl)-4-(3,4-methylenedioxyphenyl) pyridine (2) were synthesized from a chalchone precursor. 1 was more active than 2 in inhibiting the proliferation of MCF-7 and HepG2 cells, whereas HepG2 cells were more sensitive to the antiproliferative activity of these compounds compared with MCF-7 cells. The lowest IC50 value was noted for compound 1 in HepG2 cells (IC50=4.5±0.3 μM). The mechanism of action involved induction of G2/M arrest and apoptosis. Both 1 and 2 further induced downregulation of the cell cycle-associated protein cyclin D1 and upregulation of the cell cycle inhibitors p53 and p21 and the apoptosis-associated protein JNK in HepG2 cells. Compound 1 was further shown to induce phosphorylation of JNK in HepG2 cells. These results demonstrate promising cytostatic effects for the two novel anticancer compounds in human cancer cells.