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Asymmetric Synthesis and Biological Evaluation of Glycosidic Prodrugs for a Selective Cancer Therapy |
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| Authors: | Lutz?F Tietze Prof?Dr J?Marian von?Hof Birgit Krewer Michael Müller Felix Major Dr Heiko?J Schuster Dr Ingrid Schuberth Dr Frauke Alves Dr |
| Affiliation: | 1. Institut für Organische und Biomolekulare Chemie, Georg‐August‐Universit?t G?ttingen, Tammannstrasse 2, 37077 G?ttingen (Germany), Fax: (+49)?551‐39‐9476;2. Zentrum Innere Medizin, Abteilung H?matologie und Onkologie, Universit?tsklinikum und Medizinische Fakult?t, Georg‐August‐Universit?t G?ttingen, Robert‐Koch‐Stra?e 40, 37075 G?ttingen (Germany) |
| Abstract: | A severe limitation in cancer therapy is the often insufficient differentiation between malign and benign tissue using known chemotherapeutics. One approach to decrease side effects is antibody‐directed enzyme prodrug therapy (ADEPT). We have developed new glycosidic prodrugs such as (?)‐(1S)‐ 26 b based on the antibiotic (+)‐duocarmycin SA ((+)‐ 1 ) with a QIC50 value of 3500 (QIC50=IC50 of prodrug/IC50 of prodrug+enzyme) and an IC50 value for the corresponding drug (prodrug+enzyme) of 16 pM . The asymmetric synthesis of the precursor (?)‐(1S)‐ 19 was performed by arylation of the enantiomerically pure epoxide (+)‐(S)‐ 29 (≥98 % ee). |
| Keywords: | ADEPT antitumor agents duocarmycins epoxides glycosides prodrugs |