New Cathepsin Inhibitors to Explore the Fluorophilic Properties of the S2 Pocket of Cathepsin B: Design, Synthesis, and Biological Evaluation

Authors

  • Prof. Dr. Santos Fustero,

    Corresponding author
    1. Departamento de Química Orgánica, Universidad de Valencia, 46100 Burjassot (Spain), Fax: (+34) 963-544-939
    2. Laboratorio de Moléculas Orgánicas, Centro de Investigación Príncipe Felipe, 46012 Valencia (Spain)
    • Departamento de Química Orgánica, Universidad de Valencia, 46100 Burjassot (Spain), Fax: (+34) 963-544-939
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  • Dr. Vanessa Rodrigo,

    1. Laboratorio de Moléculas Orgánicas, Centro de Investigación Príncipe Felipe, 46012 Valencia (Spain)
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  • Dr. María Sánchez-Roselló,

    1. Laboratorio de Moléculas Orgánicas, Centro de Investigación Príncipe Felipe, 46012 Valencia (Spain)
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  • Dr. Carlos del Pozo,

    1. Departamento de Química Orgánica, Universidad de Valencia, 46100 Burjassot (Spain), Fax: (+34) 963-544-939
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  • Prof. Dr. Joaquín Timoneda,

    1. Departamento de Bioquímica y Biología Molecular, Universidad de Valencia, 46100 Burjassot (Spain)
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  • Maxim Frizler,

    1. Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, 53121 Bonn (Germany), Fax: (+49) 228-732567
    2. NRW International Graduate Research School Biotech-Pharma, 53105 Bonn (Germany)
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  • Dr. Mihiret T. Sisay,

    1. Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, 53121 Bonn (Germany), Fax: (+49) 228-732567
    2. Department of Life Science Informatics, B-IT, University of Bonn, 53113 Bonn (Germany)
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  • Prof. Dr. Jürgen Bajorath,

    1. Department of Life Science Informatics, B-IT, University of Bonn, 53113 Bonn (Germany)
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  • Dr. Luis P. Calle,

    1. Chemical and Physical Biology, Centro de Investigaciones Biológicas, CSIC, 28040 Madrid (Spain), Fax: (+34) 915-360-432
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  • Dr. F. Javier Cañada,

    1. Chemical and Physical Biology, Centro de Investigaciones Biológicas, CSIC, 28040 Madrid (Spain), Fax: (+34) 915-360-432
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  • Prof. Dr. Jesús Jiménez-Barbero,

    Corresponding author
    1. Chemical and Physical Biology, Centro de Investigaciones Biológicas, CSIC, 28040 Madrid (Spain), Fax: (+34) 915-360-432
    • Chemical and Physical Biology, Centro de Investigaciones Biológicas, CSIC, 28040 Madrid (Spain), Fax: (+34) 915-360-432
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  • Prof. Dr. Michael Gütschow

    Corresponding author
    1. Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, 53121 Bonn (Germany), Fax: (+49) 228-732567
    2. NRW International Graduate Research School Biotech-Pharma, 53105 Bonn (Germany)
    • Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, 53121 Bonn (Germany), Fax: (+49) 228-732567
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Abstract

original image

Fluor-in or out? Based on β,β-difluorinated cycloaliphatic amino acids, a library of new dipeptide nitriles was evaluated as human cathepsin inhibitors. The orientation of the fluorinated face relative to the protein structure of cathepsin B was elucidated by molecular modeling and NMR studies (see figure). For (R)-configured eutomers, the fluorine atoms are directed to the S2 pocket, whereas in (S)-configured distomers, the fluorinated face is solvent-exposed.

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