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A Natural Product Inspired Tetrahydropyran Collection Yields Mitosis Modulators that Synergistically Target CSE1L and Tubulin

Authors

  • Dr. Tobias Voigt,

    1. Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
    2. Technische Universität Dortmund, Fakultät Chemie, Lehrbereich Chem. Biologie, Otto-Hahn-Strasse 6, 44227 Dortmund (Germany)
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    • These authors contributed equally to this work.

  • Dr. Claas Gerding-Reimers,

    1. Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
    2. Technische Universität Dortmund, Fakultät Chemie, Lehrbereich Chem. Biologie, Otto-Hahn-Strasse 6, 44227 Dortmund (Germany)
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    • These authors contributed equally to this work.

  • M. Sc. Tuyen Thi Ngoc Tran,

    1. Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
    2. Technische Universität Dortmund, Fakultät Chemie, Lehrbereich Chem. Biologie, Otto-Hahn-Strasse 6, 44227 Dortmund (Germany)
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    • These authors contributed equally to this work.

  • M. Sc. Sabrina Bergmann,

    1. Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
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  • Dr. Hugo Lachance,

    1. Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
    2. Technische Universität Dortmund, Fakultät Chemie, Lehrbereich Chem. Biologie, Otto-Hahn-Strasse 6, 44227 Dortmund (Germany)
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  • Beate Schölermann,

    1. Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
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  • Dipl.-Ing. Andreas Brockmeyer,

    1. Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
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  • Dr. Petra Janning,

    1. Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
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  • Dr. Slava Ziegler,

    1. Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
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  • Prof. Dr. Herbert Waldmann

    Corresponding author
    1. Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
    2. Technische Universität Dortmund, Fakultät Chemie, Lehrbereich Chem. Biologie, Otto-Hahn-Strasse 6, 44227 Dortmund (Germany)
    • Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)

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  • Generous financial support by the MPG and the Fonds der Chemischen Industrie is gratefully acknowledged. We would like to thank Aymelt Itzen for helpful discussions on affinity measurements and the Dortmund Protein Facility (DPF) for cloning pOPIN-His/EGFP-CSE1L. This research was funded by the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement no. 268309 and the Max Planck Gesellschaft.

Abstract

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A Prins cyclization between a polymer-bound aldehyde and a homoallylic alcohol served as the key step in the synthesis of tetrahydropyran derivatives. A phenotypic screen led to the identification of compounds that inhibit mitosis (as seen by the accumulation of round cells with condensed DNA and membrane blebs; see picture). These compounds were termed tubulexins as they target the CSE1L protein and the vinca alkaloid binding site of tubulin.

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