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Design, synthesis, and biological evaluation of new biaryl derivatives of cycloalkyl diacetamide bearing chalcone moiety as type II c-MET kinase inhibitors

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Abstract

Many human cancers have been associated with the deregulation of the mesenchymal-epithelial transition factor tyrosine kinase (MET) receptor, a promising drug target for anticancer drug discovery. Herein, we report the discovery of a novel structure of potent chalcone-based derivatives type II c-Met inhibitors which are comparable to Foretinib (IC50 = 14 nM) as a potent reference drug. Based on our design strategy, we also expected an anti-tubulin activity for the compounds. However, the weak inhibitory effects on microtubules were confirmed by cell cycle analyses implicated that the observed cytotoxicity against HeLa cells probably was not derived from tubulin inhibition. Compounds 14q and 14k with IC50 values of 24 nM and 45 nM, respectively, demonstrated favorable inhibition of MET kinase activity, and desirable bonding interactions in the ligand-MET enzyme complex stability in molecular docking studies.

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Acknowledgements

This work was supported and funded by a grant from the Tehran University of Medical Sciences grant no. 55283. Moreover, we are truly grateful to the University of Tsukuba for conducting the biological assays.

Funding

This article was funded by Tehran University of Medical Sciences, 55283.

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Authors and Affiliations

  1. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    Somayeh Salarinejad, Loghman Firoozpour & Alireza Foroumadi

  2. Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran

    Soheila Seyfi, Setareh Moghimi, Loghman Firoozpour & Alireza Foroumadi

  3. Institute of Life and Environmental Sciences, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki, 305-8572, Japan

    Seiko Hayashi & Takeo Usui

  4. Department of Medicinal Chemistry, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Mahsa Toolabi

  5. Department of Biotechnology, Faculty of Science, Bartin University, 74100, Bartin, Turkey

    Parham Taslimi

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  1. Somayeh Salarinejad
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Correspondence to Takeo Usui or Alireza Foroumadi.

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Salarinejad, S., Seyfi, S., Hayashi, S. et al. Design, synthesis, and biological evaluation of new biaryl derivatives of cycloalkyl diacetamide bearing chalcone moiety as type II c-MET kinase inhibitors. Mol Divers (2024). https://doi.org/10.1007/s11030-024-10807-x

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