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

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.

Progress in Research on the Role of Flavonoids in Lung Cancer

“…Flavones are commonly found in many fruits and plant foods [21]. The main flavones are apigenin, luteolin and diosmetin which showed potent inhibitory effects on the proliferation, activation of apoptosis and cell cycle regulation, but also invasion and metastasis [21].…”

“…Flavones are commonly found in many fruits and plant foods [21]. The main flavones are apigenin, luteolin and diosmetin which showed potent inhibitory effects on the proliferation, activation of apoptosis and cell cycle regulation, but also invasion and metastasis [21]. Dietary flavones may serve as preventive/therapeutic agents against different human cancers due to their interfering capacity with epigenetic pathways [22].…”

A candidate gene identified in converting platycoside E to platycodin D from Platycodon grandiflorus by transcriptome and main metabolites analysis

“…From the chemical structure of platycodin D and platycoside E, it can be predicted that there are enzymes which can catalyze degradation of glycosyl group from PE to PD. Two extracellular experiments showed that β-D-glucosidase from Aspergillus usamii and Caldicellulosiruptor bescii can successfully catalyze conversion of PE and platycodin D3 into PD under optimal reactions conditions 18 , 19 . In this study we attempt to find out appropriate candidate genes encoding enzymes involving in conversion of PE, platycodin D3 into PD in traditional Chinese medicinal plant P. grandiflorus .…”

Single Crystal X-Ray Structure for the Disordered Two Independent Molecules of Novel Isoflavone: Synthesis, Hirshfeld Surface Analysis, Inhibition and Docking Studies on IKKβ of 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6,7-dimethoxy-4H-chromen-4-one

“…The three-dimensional structure of IκB kinaseβ (IKKβ) was adopted from a protein data bank deposited as 4KIK.pdb [40]. The detailed experimental procedures followed to the methods previously reported [41].…”