Discovery of 3,4,6-Triaryl-2-pyridones as Potential Anticancer Agents that Promote ROS-Independent Mitochondrial-Mediated Apoptosis in Human Breast Carcinoma Cells

Abstract

A library of 3,4,6-triaryl-2-pyridones has been synthesized using multicomponent reaction (MCR) of substituted acetophenones, benzaldehydes and phenyl acetamides. All the synthesized compounds were evaluated for their anti-breast cancer activity, in vitro in ER+ and ER- cancer cell lines, wherein, compounds (4-(3,4-dimethoxyphenyl)-6-(4-methoxyphenyl)-3-phenylpyridin-2(1H)–one) (11) and (3,6-bis(4-methoxyphenyl)-4-(4-(2-(piperidin-1-yl)ethoxy)phenyl)pyridin-2(1H)-one) (35) were found to be the most active with best safety profile towards non-cancer originated HEK-293 cells. Cell cycle analysis showed that the compounds 11 and 35 induced statistically significant arrest of cells in G1 phase and reduction in S-phase cells in a dose-dependent manner. Compound 11, unlike compound 35 exerts breast cancer cell membrane specific action as observed with LDH assay, whereas compound 35 induced ROS-independent mitochondrial-mediated apoptosis in breast cancer cell line, MDA-MB-231. Apoptotic activity of compound 35 was also confirmed by DNA fragmentation and by expression of pro-apoptotic genes, BAD, BAK, and BimL. Compound 35 is about five times safer than its effective IC50 values in MDA-MB-231 cell line, which makes it a non-toxic breast cancer therapeutic agent.