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 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 IC50 values in MDA‐MB‐231 cell line, which makes it a non‐toxic breast cancer therapeutic agent.

Visible Light-Promoted Green and Sustainable Approach for One-Pot Synthesis of 4,4’-(Arylmethylene)bis(1H-pyrazol-5-ols), In Vitro Anticancer Activity, and Molecular Docking with Covid-19 Mpro

“…To achieve our purpose, all the synthesized 4,4′-(arylmethylene)bis(1H-pyrazol-5-ol) derivatives were evaluated in vitro for their anticancer activity against a panel of five different human cancer cell lines, breast cancer (MCF-7 and MDA-MB-231), cervical cancer (Hela cells), endometrial cancer (Ishikawa cell line), and prostate cancer cell lines (PC-3) and compared with Tamoxifen (TAM) using MTT assay ( Figure 3 and 4 ). 45 Tamoxifen 45b , 45c , 46 is an effective therapy used to treat estrogen receptor-positive (ER + Ve) breast cancer. Therefore, we selected Tamoxifen as a positive control drug to compare the activity with synthesized compounds against ER + Ve cancer cell lines (MCF-7).…”

“…Furthermore, we evaluated these compounds to explore their potential activity against cancer of other organs or tissues such as endometrial adenocarcinoma (Ishikawa), cervical cancer (Hela), and prostate cancer (PC-3). To achieve our purpose, all the synthesized 4,4′-(arylmethylene)­bis­(1H-pyrazol-5-ol) derivatives were evaluated in vitro for their anticancer activity against a panel of five different human cancer cell lines, breast cancer (MCF-7 and MDA-MB-231), cervical cancer (Hela cells), endometrial cancer (Ishikawa cell line), and prostate cancer cell lines (PC-3) and compared with Tamoxifen (TAM) using MTT assay (Figure and ) . Tamoxifen ,, is an effective therapy used to treat estrogen receptor-positive (ER + Ve) breast cancer.…”

Bioactive 2-pyridone-containing heterocycle syntheses using multicomponent reactions

“…In this regard, 3,4,6-triaryl-2(1 H )-pyridones 13a–p were synthesized in 58–82% yields through a one-pot three-component reaction of aromatic aldehydes 1, substituted acetophenones 7, and phenyl acetamides 12 in the presence of sodium hydride in DMSO at 130 °C ( Scheme 2 ). 46 All synthesized compounds 13a–p were evaluated for their in vitro anticancer activity against MCF-7 and MDA-MB-231 breast cancer cell lines using the MTT method in the presence of Nolvadex (tamoxifen citrate) as a standard drug. Data shown are average ± SD of two independent experiments.…”

Unravelling the Design and Mechanism: Potential of Substituted Quinolines as PASTA subunit 4 Inhibitors for Antimicrobial Activity

“…Indoles, oxadiazoles, pyrroles, quinolines, pyridines, quinazolines, quinoxalines, pyridones and others are a few of the significant N-containing heterocycles. [29][30][31][32] Since these N-containing heterocycles have previously shown to exhibit a wide range of biological activity, like pyridone derivatives have proved themselves to be a potent anti-breast cancer agent proving themselves to be a malady for women, [33] they have been regarded as special class of chemicals that are biologically active and are used in medicinal chemistry. [34,35] In a pool of such diverse N-containing heterocyles, quinoline is one such heterocycle, which is made up of a single pyridine ring fused to a benzene ring.…”