Abstract
A group of styrylquinolines were synthesized and tested for their anti-proliferative activity. Anti-proliferative activity was evaluated against the human colon carcinoma cell lines that had a normal expression of the p53 protein (HCT116 p53+/+) and mutants with a disabled TP53 gene (HCT116 p53-/-) and against the GM 07492 normal human fibroblast cell line. A SAR study revealed the importance of Cl and OH as substituents in the styryl moiety. Several of the compounds that were tested were found to have a marked anti-proliferative activity that was similar to or better than doxorubicin and were more active against the p53 null than the wild type cells. The cellular localization tests and caspase activity assays suggest a mechanism of action through the mitochondrial pathway of apoptosis in a p53-independent manner. The activity of the styrylquinoline compounds may be associated with their DNA intercalating ability.
Highlights
Styrylquinolines are interesting quinoline-related compounds that have a broad spectrum of biological activity [1,2,3,4,5,6,7]
Based on our experience in the design and synthesis of biologically active stryrylquinolines and their structural similarity to CP-31398, we decided to screen the series of compounds on human colon cancer lines, wild-type and p53 negative
The compounds that were used in this study were obtained during our search for active styrylquinolines as published recently [2,7,28,29,30,31,32,33]
Summary
Styrylquinolines are interesting quinoline-related compounds that have a broad spectrum of biological activity [1,2,3,4,5,6,7]. The anti-proliferative effect of quinoline-5,8-diones and styrylquinoline-carboxylic acids on tumor cell lines have been observed [8,9]. Among them the analog of II (R = H, R1 = OH) shown activity at micromolar level IC50 = 1.5 μM (HCT116 p53+/+ cell line) [9] Another very important group to be mentioned here are quinolinediones. This moiety is the main fragment of lavendamycin and related compounds, which are known for their broad spectrum of activity and a series of 7-amino-quinaldine-5,8-diones whose anti-proliferative activity has been reported [8,10,11,12,13]. PLOS ONE | DOI:10.1371/journal.pone.0142678 November 23, 2015
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