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Design, synthesis, and biological evaluation of polyphenols with 4,6-diphenylpyrimidin-2-amine derivatives for inhibition of Aurora kinase A

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Abstract

Background

Several 4,6-diarylpyrimidin-2-amine derivatives show anticancer properties. However, their mode of action is not fully characterized. To develop potent anticancer chemotherapeutic agents, we designed and synthesized 25 4,6-diphenylpyrimidin-2-amine derivatives containing a guanidine moiety.

Methods

Clonogenic long-term survival assays were performed to screen anticancer compounds. To derive the structural conditions showing good cytotoxicities against cancer cells, quantitative structure-activity relationships (QSAR) were calculated. Biological activities were determined by flow cytometry for cell cycle analysis and by immunoblot analysis for the detection of Aurora kinase A (AURKA) activity. Because 2-(2-Amino-6-(2,4-dimethoxyphenyl)pyrimidin-4-yl) phenol (derivative 12) selectively inhibited AURKA activity from the kinome assay, in silico docking experiments were performed to elucidate the molecular binding mode between derivative 12 and AURKA.

Results

The pharmacophores were derived based on the QSAR calculations. Derivative 12 inhibited AURKA activity and reduced phosphorylation of AURKA at Thr283 in HCT116 human colon cancer cells. Derivative 12 caused the accumulation of the G2/M phase of the cell cycle and triggered the cleavages of caspase-3, caspase −7, and poly(ADP-ribose) polymerase. The binding energies of 30 apo-AURKA – derivative 12 complexes obtained from in silico docking ranged from −16.72 to −11.63 kcal/mol.

Conclusions

Derivative 12 is an AURKA inhibitor, which reduces clonogenicity, arrests the cell cycle at the G2/M phase, and induces caspase-mediated apoptotic cell death in HCT116 human colon cancer cells. In silico docking demonstrated that derivative 12 binds to AURKA well. The structure-activity relationship calculations showed hydrophobic substituents and 1-naphthalenyl group at the R2 position increased the activity. The existence of an H-bond acceptor at C-2 of the R1 position increased the activity, too.

Derivative 12 inhibits Aurora kinase A activity and causes the G2/M phase arrest of the cell cycle

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Abbreviations

AURKA :

Aurora kinase A

AURKB :

Aurora kinase B

AURKC :

Aurora kinase C

CLSA :

Clonogenic long-term survival assay

CoMFA :

Comparative molecular field analysis

CoMSIA :

Comparative molecular similarity indices analysis

GI 50 :

Half-maximal growth inhibitory concentrations

HR/MS :

High-resolution mass spectrometry

PARP :

Poly(ADP-ribose) polymerase

QSAR :

Quantitative structure-activity relationships

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Acknowledgments

This work was supported by the Konkuk University Research Support Program (YHL).

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Authors and Affiliations

  1. Department of Biological Sciences, Sanghuh College of Life Sciences, Konkuk University, Seoul, 05029, Republic of Korea

    Young Han Lee & Soon Young Shin

  2. Cancer and Metabolism Institute, Konkuk University, Seoul, 05029, Republic of Korea

    Young Han Lee & Soon Young Shin

  3. Division of Bioscience and Biotechnology, BMIC, Konkuk University, Seoul, 05029, Republic of Korea

    Jihyun Park, Seunghyun Ahn, Youngshim Lee, Junho Lee & Yoongho Lim

  4. Department of Applied Chemistry, Dongduk Women’s University, Seoul, 02748, Republic of Korea

    Dongsoo Koh

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  1. Young Han Lee
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  5. Junho Lee
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Contributions

YHL: designed the experiments and wrote the manuscript. JP, YLee, JL, SYS: conducted the experiments. SA: synthesized chemicals. DK and YLim: supervised the study, analyzed the data, and edited the manuscript. All authors read and approved the final manuscript.

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Correspondence to Dongsoo Koh or Yoongho Lim.

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Lee, Y.H., Park, J., Ahn, S. et al. Design, synthesis, and biological evaluation of polyphenols with 4,6-diphenylpyrimidin-2-amine derivatives for inhibition of Aurora kinase A. DARU J Pharm Sci 27, 265–281 (2019). https://doi.org/10.1007/s40199-019-00272-5

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  • DOI: https://doi.org/10.1007/s40199-019-00272-5

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