Discovering Novel α-aminoacyl-Containing Proline Derivatives with Potent and Selective Inhibitory Activity Against Dipeptidyl Peptidase IV: Design, Synthesis, Biological Evaluation, and Molecular Modeling

Authors

  • Xiaodong Zhang,

    1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China
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    • These authors contributed equally to this work.

  • Jiang Wang,

    1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China
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    • These authors contributed equally to this work.

  • Mingbo Su,

    1. National Center for Drug Screening, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Shanghai 201303, China
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    • These authors contributed equally to this work.

  • Zeng Li,

    1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China
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  • Jingya Li,

    1. National Center for Drug Screening, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Shanghai 201303, China
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  • Jia Li,

    Corresponding author
    1. National Center for Drug Screening, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Shanghai 201303, China
      Corresponding author: Hong Liu, hliu@mail.shcnc.ac.cn
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  • Hong Liu

    Corresponding author
    1. National Center for Drug Screening, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Shanghai 201303, China
      Corresponding author: Hong Liu, hliu@mail.shcnc.ac.cn
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Corresponding author: Hong Liu, hliu@mail.shcnc.ac.cn

Abstract

On the basis of the enzyme-binding features of known potent inhibitors of dipeptidyl peptidase IV, novel α-aminoacyl-containing proline analogs (8Aa–8Ak, 8Ba–8Bj, 8Ca–8Ck, and 8Da–8Di) with the S configuration were designed, synthesized, and their activity profiled. Their structural features were determined by nuclear magnetic resonance (NMR) spectroscopy, low- and high-resolution mass spectroscopy. Five compounds (8Aa, 8Aj, 8Ch, 8Ck, and 8Dc) were shown to have promising inhibitory activities against dipeptidyl peptidase IV. Two of them, compounds 8Aa and 8Aj inhibited dipeptidyl peptidase IV with IC50 values of 4.56 and 8.4 μm, respectively, and displayed no inhibition at other dipeptidyl peptidase IV. The possible binding modes of compounds 6, 7, 8Aa, and 8Aj with dipeptidyl peptidase IV were also explored by molecular docking simulation. This study provides promising new templates for the further development of antidiabetic agents.

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