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

original image

Seco-Cyclopropabenzindol(CBI)-Verbindungen, die von Duocarmycin abgeleitet sind, binden an DNA und an eine Aldehyddehydrogenase (ALDH1A1) in Lungenkrebszellen, wie bereits zuvor gezeigt wurde. Die Entfernung der DNA-bindenden Indoleinheit resultiert in einer CBI-Verbindung, die nicht an DNA in Zellen bindet, aber immer noch cytotoxisch ist. Diese CBI-Verbindung hat eine erhöhte Affinität für ALDH1A1. Rh=Rhodamin.

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