The Two Faces of Potent Antitumor Duocarmycin-Based Drugs: A Structural Dissection Reveals Disparate Motifs for DNA versus Aldehyde Dehydrogenase 1 Affinity†
Tanja Wirth
Department Chemie, Center for Integrated Protein Science CIPSM, Institute of Advanced Studies IAS, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching (Germany)
Search for more papers by this authorDr. Galina F. Pestel
Institute of Organic and Biomolecular Chemistry, Georg-August-Universität Göttingen, Tammannstrasse 2, 37033 Göttingen (Germany)
Search for more papers by this authorVanessa Ganal
Max Planck Institute of Psychiatry, 80804 Munich (Germany)
Search for more papers by this authorThomas Kirmeier
Max Planck Institute of Psychiatry, 80804 Munich (Germany)
Search for more papers by this authorDr. Ingrid Schuberth
Institute of Organic and Biomolecular Chemistry, Georg-August-Universität Göttingen, Tammannstrasse 2, 37033 Göttingen (Germany)
Search for more papers by this authorTheo Rein
Max Planck Institute of Psychiatry, 80804 Munich (Germany)
Search for more papers by this authorCorresponding Author
Professor Lutz F. Tietze
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)
Search for more papers by this authorCorresponding Author
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)
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)
Search for more papers by this authorTanja Wirth
Department Chemie, Center for Integrated Protein Science CIPSM, Institute of Advanced Studies IAS, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching (Germany)
Search for more papers by this authorDr. Galina F. Pestel
Institute of Organic and Biomolecular Chemistry, Georg-August-Universität Göttingen, Tammannstrasse 2, 37033 Göttingen (Germany)
Search for more papers by this authorVanessa Ganal
Max Planck Institute of Psychiatry, 80804 Munich (Germany)
Search for more papers by this authorThomas Kirmeier
Max Planck Institute of Psychiatry, 80804 Munich (Germany)
Search for more papers by this authorDr. Ingrid Schuberth
Institute of Organic and Biomolecular Chemistry, Georg-August-Universität Göttingen, Tammannstrasse 2, 37033 Göttingen (Germany)
Search for more papers by this authorTheo Rein
Max Planck Institute of Psychiatry, 80804 Munich (Germany)
Search for more papers by this authorCorresponding Author
Professor Lutz F. Tietze
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)
Search for more papers by this authorCorresponding Author
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)
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)
Search for more papers by this authorWe 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.
Graphical Abstract
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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