Photoactivatable Prodrugs of Highly Potent Duocarmycin Analogues for a Selective Cancer Therapy

Authors

  • Prof. Lutz F. Tietze,

    Corresponding author
    1. Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen (Germany), Fax: (+49) 551-39-9476
    • Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen (Germany), Fax: (+49) 551-39-9476
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  • Dr. Michael Müller,

    1. Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen (Germany), Fax: (+49) 551-39-9476
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  • Svenia-C. Duefert,

    1. Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen (Germany), Fax: (+49) 551-39-9476
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  • Dr. Kianga Schmuck,

    1. Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen (Germany), Fax: (+49) 551-39-9476
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  • Dr. Ingrid Schuberth

    1. Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen (Germany), Fax: (+49) 551-39-9476
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Abstract

A main problem of common cancer chemotherapy is the occurrence of severe side effects caused by insufficient selectivity of the applied drugs. A possible concept to overcome this limitation is light-driven prodrug monotherapy. The synthesis as well as photochemical and biological evaluation of new photoactivatable prodrugs is described. Best results were obtained with prodrug (S,S)-7 a. The photochemical labile protecting groups in (S,S)-7 a can easily be removed by irradiation with UV-A light in 30 min with a power of only 2 J cm−2. The determination of the in vitro cytotoxicity by using an HTCFA-test reveals a QIC50 value of 8200 and the prodrug is more than two million times less cytotoxic than the corresponding seco-drug (−)-(S,S)-5 with an IC50 value of about 110 fM. The big therapeutic window makes (S,S)-7 a very suitable for its use in selective cancer therapy.

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