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Discovery of 3,4,6‐Triaryl‐2‐pyridones as Potential Anticancer Agents that Promote ROS‐Independent Mitochondrial‐Mediated Apoptosis in Human Breast Carcinoma Cells
Author(s) -
Ansari Mohammad Imran,
Arun Ashutosh,
Hussain Mohammad Kamil,
Konwar Rituraj,
Hajela Kanchan
Publication year - 2016
Publication title -
chemistryselect
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.437
H-Index - 34
ISSN - 2365-6549
DOI - 10.1002/slct.201600893
Subject(s) - apoptosis , cell culture , cancer cell , chemistry , in vitro , dna fragmentation , cell cycle checkpoint , cancer research , ic50 , cell cycle , programmed cell death , breast cancer , cancer , biology , biochemistry , genetics
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 11 (4‐(3,4‐dimethoxyphenyl)‐6‐(4‐methoxyphenyl)‐3‐phenylpyridin‐2(1H)‐one) and 35 (3,6‐bis(4‐methoxyphenyl)‐4‐(4‐(2‐(piperidin‐1‐yl) ethoxy)phenyl)pyridin‐2(1H)‐one) 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 IC 50 values in MDA‐MB‐231 cell line, which makes it a non‐toxic breast cancer therapeutic agent.