Design, Synthesis and Biological Evaluation of Peptidyl Epoxyketone Proteasome Inhibitors Composed of β-amino Acids

Authors

  • Jiankang Zhang,

    1. ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
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    • These authors contributed equally to this work.
  • Mengmeng Han,

    1. National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
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    • These authors contributed equally to this work.
  • Xiaodong Ma,

    1. ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
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  • Lei Xu,

    1. National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
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  • Jiayi Cao,

    1. National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
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  • Yubo Zhou,

    1. National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
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  • Jia Li,

    1. National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
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  • Tao Liu,

    Corresponding author
    1. ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
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  • Yongzhou Hu

    Corresponding author
    1. ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
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Abstract

A series of novel di- and tripeptidyl epoxyketone derivatives composed of β-amino acids were designed, synthesized and evaluated for their proteasome inhibitory activities and anti-proliferation activities against two multiple myeloma cell lines RPMI 8226 and NCI-H929 and normal cells (peripheral blood mononucleated cells). Among these tested compounds, tripeptidyl analogues showed much more potent activities than dipeptides, and four tripeptidyl compounds exhibited proteasome inhibitory activities with IC50 values ranging from 0.97 ± 0.05 to 1.85 ± 0.11 μm. In addition, all the four compounds showed anti-proliferation activities with IC50 values at low micromolar levels against two multiple myeloma cell lines and weak activities against normal cells. Furthermore, Western blot analysis was performed to verify the proteasome inhibition induced by compounds 21d and 21e. All the experimental results validated that the β-amino acid building block has the potential for the development of proteasome inhibitors.

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