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Design, synthesis and antiproliferative activity of ACY-1215 analogs as potent selective histone deacetylases 6 inhibitors

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Abstract

Histone deacetylase 6 (HDAC6) plays an important role in cancer treatment, and the development of selective HDAC6 inhibitors (sHDAC6is) attracts more and more attention in recent years. In this research, a series of ACY-1215 analogs based on diphenylpyrimidine scaffold were designed and synthesized. Among these, the most potent compound 7-((4, 6-diphenylpyrimidin-2-yl)amino)-N-hydroxyheptanamide (11a) inhibited HDAC6 with IC50 of 3.8 nM and showed 26~fold selectivity over HDAC1, better than those of ACY-1215. In cellular assay, these diphenylpyrimidines exhibited promising antiproliferative activities against different tumor cell lines. Altogether, this work highlighted the therapeutic potential of diphenylpyrimidine-inspired sHDAC6 inhibitors and provides a valuable lead compound for the discovery of novel antitumor agents.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81903464) and the Natural Science Basic Research Plan in Shaanxi Province of China (2020JQ-284).

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Authors and Affiliations

  1. Department of Pharmacy, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, 450000, PR China

    Hongfei Duan

  2. Shaanxi Key Labotory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, 712100, PR China

    Jiayun Wang, Guoliang Gong, Xin Chen & Xinyang Chen

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  1. Hongfei Duan
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  4. Xin Chen
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Correspondence to Xin Chen.

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Duan, H., Wang, J., Gong, G. et al. Design, synthesis and antiproliferative activity of ACY-1215 analogs as potent selective histone deacetylases 6 inhibitors. Med Chem Res 32, 2432–2441 (2023). https://doi.org/10.1007/s00044-023-03150-7

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  • DOI: https://doi.org/10.1007/s00044-023-03150-7

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