Selective Treatment of Cancer: Synthesis, Biological Evaluation and Structural Elucidation of Novel Analogues of the Antibiotic CC-1065 and the Duocarmycins

Authors

  • Lutz F. Tietze Prof. Dr. Dr. h.c.,

    1. Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany, Fax: (+49) (0)551-399476
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  • Felix Major Dr.,

    1. Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany, Fax: (+49) (0)551-399476
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  • Ingrid Schuberth Dr.,

    1. Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany, Fax: (+49) (0)551-399476
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  • Dirk A. Spiegl Dipl.-Chem.,

    1. Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany, Fax: (+49) (0)551-399476
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  • Birgit Krewer Dipl.-Chem.,

    1. Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany, Fax: (+49) (0)551-399476
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  • Katja Maksimenka Dipl.-Chem.,

    1. Institut für Organische Chemie, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074 Würzburg, Germany
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  • Gerhard Bringmann Prof. Dr. Dr. h.c.,

    1. Institut für Organische Chemie, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074 Würzburg, Germany
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  • Jörg Magull Prof. Dr.

    1. Institut für Anorganische Chemie, Georg-August-Universität Göttingen, Tammannstrasse 4, 37077 Göttingen, Germany
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Abstract

Novel diastereomerically pure β-D-galactosidic prodrugs (+)-12 ae of the cytotoxic antibiotics CC-1065 and the duocarmycins were prepared for an antibody directed enzyme prodrug therapy (ADEPT) using 4 as a substrate via a radical cyclization to give rac-5 and rac-6 followed by a chromatographic resolution of the enantiomers of rac-5, glycosidation and linkage to the DNA-binding units 10 ae. These only slightly toxic compounds can be toxified enzymatically by an antibody–β-D-galactosidase conjugate at the surface of malignant cells to give the cytotoxic drugs, which then alkylate DNA. The new prodrugs were tested in in vitro cytotoxicity assays showing excellent QIC50 values of 4800 and 4300 for (+)-12 a and (+)-12 b, respectively. The absolute configuration of precursor (+)-5 was determined by comparison of the experimental CD spectrum with the theoretically predicted CD spectra and by X-ray structure analysis.

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