The synthesis and anticancer activity of 2-styrylquinoline derivatives. A p53 independent mechanism of action

• Published in: European journal of medicinal chemistry 2019-09, Vol.177, p.338-349
• Main Authors: Mrozek-Wilczkiewicz, Anna, Kuczak, Michał, Malarz, Katarzyna, Cieślik, Wioleta, Spaczyńska, Ewelina, Musiol, Robert
• Format: Article
• Language: English
• Subjects: 2-Styrylquinoline derivatives; Anticancer activity; Apoptosis; Cell cycle inhibition; p53 protein; Reactive oxygen species
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.05.061

A series of styrylquinolines was designed and synthesized based on the four main quinoline scaffolds including oxine, chloroxine and quinolines substituted with a hydroxyl group or chlorine atom at the C4 position. All of the compounds were tested for their anticancer activity on wild-type colon cancer cells (HCT 116) and those with a p53 deletion. Analysis of SAR revealed the importance of electron-withdrawing substituents in the styryl part and chelating properties in the quinoline ring. The compounds that were more active were also tested on a panel of four cancer cell lines with mutations in TP53 tumor suppressor gene. The results suggest that styrylquinolines induce cell cycle arrest and activate a p53-independent apoptosis. The apparent mechanism of action was studied for the most promising compounds, which produced reactive oxygen species and changed the cellular redox balance. [Display omitted] •Diverse series of styrylquinolines designed and tested for the anticancer activity.•The SAR indicates importance of electron-withdrawing groups and metal chelation site.•The anti-proliferative effect is correlated with the overproduction of intracellular ROS.•The oxidative stress and the ROS-related pathways lead to apoptosis in the p53 independent manner.