Synthesis and biological evaluation of selected 7-azaindole derivatives as CDK9/Cyclin T and Haspin inhibitors

Abstract

The 7-azaindole scaffold attracts attention due to its value in the design of inhibitors of diseases related protein kinases. However, this scaffold has not been evaluated against Haploid germ cell-specific nuclear protein kinase (Haspin). Herein, we report the synthesis of a select set of 7-azaindole derivatives and their evaluation against Haspin. The compounds were also evaluated against CDK9/Cyclin T kinase. The synthesis of 7-azaindole derivatives was achieved through Suzuki coupling using appropriate halogenated 7-azaindole and boronic acids. Seven of the screened compounds exhibited activity as CDK9/Cyclin T and/or Haspin inhibitors in a nanomolar to low micromolar range. The most promising dual inhibiting compound 18c, exhibited an inhibitory potential of 0.206 µM against CDK9/Cyclin T and 0.118 µM against Haspin. The dual inhibition of CDK9/Cyclin T and Haspin could afford a potentially potent antimitotic agent of value in further anticancer studies.

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Acknowledgements

The authors are grateful to Dr. D.Otto and Dr. J.Jordaan of the SASOL Centre for Chemistry, North-West University, for recording the MS and NMR spectra, respectively. The authors thank the “Ligue contre le Cancer du Grand-Ouest” comity, (districts: 29, 22, 56, 35, 45, and 79), Cancéropôle Grand Ouest (axis: natural sea products in cancer treatment network), IBiSA (French Infrastructures en sciences du vivant: biologie, santé et agronomie) and Biogenouest (Western France life science and environment core facility network) for supporting the KISSf screening facility (FR2424, CNRS and Sorbonne Université), Roscoff, France.

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Correspondence to Lesetja J. Legoabe.

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Stéphane Bach is a founder and member of the SAB of SeaBeLife Biotech (Roscoff, France). This company is developing novel therapies for treating liver and kidney acute disorders. This work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that they have no conflict of interest

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Pieterse, L., Legoabe, L.J., Beteck, R.M. et al. Synthesis and biological evaluation of selected 7-azaindole derivatives as CDK9/Cyclin T and Haspin inhibitors. Med Chem Res 29, 1449–1462 (2020). https://doi.org/10.1007/s00044-020-02560-1

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Keywords

  • Protein kinases
  • 7-Azaindole
  • anticancer
  • CDK9/ Cyclin T
  • Haspin