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Inhibitory Effect of Synthetic Flavone Derivatives on Pan-Aurora Kinases: Induction of G2/M Cell-Cycle Arrest and Apoptosis in HCT116 Human Colon Cancer Cells

1
Department of Biological Sciences, Sanghuh College of Life Science s, Konkuk University, Seoul 05029, Korea
2
Cancer and Metabolism Institute, Konkuk University, Seoul 05029, Korea
3
Division of Bioscience and Biotechnology, BMIC, Konkuk University, Seoul 05029, Korea
4
Department of Applied Chemistry, Dongduk Women’s University, Seoul 02748, Korea
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(12), 4086; https://doi.org/10.3390/ijms19124086
Received: 28 November 2018 / Revised: 14 December 2018 / Accepted: 14 December 2018 / Published: 17 December 2018
(This article belongs to the Special Issue Polyphenols: Nutrition, Physiology, Metabolism and Health Benefits)
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Abstract

Members of the aurora kinase family are Ser/Thr kinases involved in regulating mitosis. Multiple promising clinical trials to target aurora kinases are in development. To discover flavones showing growth inhibitory effects on cancer cells, 36 flavone derivatives were prepared, and their cytotoxicity was measured using a long-term clonogenic survival assay. Their half-maximal growth inhibitory effects against HCT116 human colon cancer cells were observed at the sub-micromolar level. Pharmacophores were derived based on three-dimensional quantitative structure–activity calculations. Because plant-derived flavones inhibit aurora kinase B, we selected 5-methoxy-2-(2-methoxynaphthalen-1-yl)-4H-chromen-4-one (derivative 31), which showed the best half-maximal cell growth inhibitory effect, and tested whether it can inhibit aurora kinases in HCT116 colon cancer cells. We found that derivative 31 inhibited the phosphorylation of aurora kinases A, aurora kinases B and aurora kinases C, suggesting that derivative 31 is a potential pan-aurora kinase inhibitor. The results of our analysis of the binding modes between derivative 31 and aurora A and aurora B kinases using in-silico docking were consistent with the pharmacophores proposed in this study. View Full-Text
Keywords: flavones; colon cancer; clonogenicity; apoptosis; aurora kinases; quantitative structure–activity relationship; in-silico docking flavones; colon cancer; clonogenicity; apoptosis; aurora kinases; quantitative structure–activity relationship; in-silico docking
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Shin, S.Y.; Lee, Y.; Kim, B.S.; Lee, J.; Ahn, S.; Koh, D.; Lim, Y.; Lee, Y.H. Inhibitory Effect of Synthetic Flavone Derivatives on Pan-Aurora Kinases: Induction of G2/M Cell-Cycle Arrest and Apoptosis in HCT116 Human Colon Cancer Cells. Int. J. Mol. Sci. 2018, 19, 4086.

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