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The Two Faces of Potent Antitumor Duocarmycin-Based Drugs: A Structural Dissection Reveals Disparate Motifs for DNA versus Aldehyde Dehydrogenase 1 Affinity

Authors

  • Tanja Wirth,

    1. Department Chemie, Center for Integrated Protein Science CIPSM, Institute of Advanced Studies IAS, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching (Germany)
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  • Dr. Galina F. Pestel,

    1. Institute of Organic and Biomolecular Chemistry, Georg-August-Universität Göttingen, Tammannstrasse 2, 37033 Göttingen (Germany)
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  • Vanessa Ganal,

    1. Max Planck Institute of Psychiatry, 80804 Munich (Germany)
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  • Thomas Kirmeier,

    1. Max Planck Institute of Psychiatry, 80804 Munich (Germany)
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  • Dr. Ingrid Schuberth,

    1. Institute of Organic and Biomolecular Chemistry, Georg-August-Universität Göttingen, Tammannstrasse 2, 37033 Göttingen (Germany)
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  • Theo Rein,

    1. Max Planck Institute of Psychiatry, 80804 Munich (Germany)
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  • Professor Lutz F. Tietze,

    Corresponding author
    1. Institute of Organic and Biomolecular Chemistry, Georg-August-Universität Göttingen, Tammannstrasse 2, 37033 Göttingen (Germany)
    • Professor Lutz F. Tietze, Institute of Organic and Biomolecular Chemistry, Georg-August-Universität Göttingen, Tammannstrasse 2, 37033 Göttingen (Germany)

      Professor Stephan A. Sieber, Department Chemie, Center for Integrated Protein Science CIPSM, Institute of Advanced Studies IAS, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching (Germany)

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  • Professor Stephan A. Sieber

    Corresponding author
    1. Department Chemie, Center for Integrated Protein Science CIPSM, Institute of Advanced Studies IAS, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching (Germany)
    • Professor Lutz F. Tietze, Institute of Organic and Biomolecular Chemistry, Georg-August-Universität Göttingen, Tammannstrasse 2, 37033 Göttingen (Germany)

      Professor Stephan A. Sieber, Department Chemie, Center for Integrated Protein Science CIPSM, Institute of Advanced Studies IAS, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching (Germany)

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  • We thank Mona Wolff and Anna-Maria Werner for excellent scientific support and Nina Bach and Katrin Lorenz-Baath for scientific discussions. S.A.S. was supported by the Deutsche Forschungsgemeinschaft SFB749, SFB1035, FOR1406, an ERC starting grant and the Center for Integrated Protein Science Munich CIPSM. T.W. thanks the TUM Graduate School for project funding. L.F.T. is thankful to the DFG, the VW-foundation, the State of Lower Saxony, and the Fonds der Chemischen Industrie for financial support.

Abstract

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Duocarmycin-derived seco-cyclopropabenzindole (CBI) drugs have been shown to bind DNA and an aldehyde dehydrogenase (ALDH1A1) in lung cancer cells. The removal of the DNA-binding indole moiety results in a CBI compound that does not bind to DNA in whole cells but still exhibits remarkable cytotoxicity. This CBI compound has an increased affinity for ALDH1A1. Rh=rhodamine.

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