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Design, synthesis, and biological evaluation of 4-(1H-1,2,3-triazol-1-yl)benzamides as HSP90 inhibitors

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Abstract

Heat shock protein 90 (HSP90) is a promising anticancer drug target, which could be employed to construct HSP90 inhibitors-based drug conjugates for selective tumor therapy. Herein, a series of 4-(1H-1,2,3-triazol-1-yl)benzamides were rationally designed, synthesized as HSP90 inhibitors, and their structures were characterized by 1H NMR, 13C NMR, and HR-MS. Preliminary HSP90 binding assay showed that compounds 6b, 6l, 6m, 6n, 6t, and 6u exhibited significant HSP90α binding affinity. Among these selected compounds, 6u displayed the most potent anti-proliferative activities and particularly in Capan-1 cell line. Molecular modeling studies also confirmed possible mode of interaction between 6u and the binding sites of HSP90 by hydrogen bond and hydrophobic interactions. Above all, these encouraging data indicated that 6u could be used as a HSP90 inhibitor for further study and helped the recognition of the 4-(1H-1,2,3-triazol-1-yl)benzamide motif as a new scaffold for HSP90 inhibitors.

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Acknowledgements

This research was funded by the Fundamental Research Funds for the Central Universities and the National Natural Science Foundation of China, Grant Numbers 22077034 and 82104000.

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  1. Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, People’s Republic of China

    Tingting He, Shulei Zhu & Wei Lu

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  1. Tingting He
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Correspondence to Shulei Zhu or Wei Lu.

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He, T., Zhu, S. & Lu, W. Design, synthesis, and biological evaluation of 4-(1H-1,2,3-triazol-1-yl)benzamides as HSP90 inhibitors. Mol Divers 27, 239–248 (2023). https://doi.org/10.1007/s11030-022-10423-7

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  • DOI: https://doi.org/10.1007/s11030-022-10423-7

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