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Tietze, Lutz F.; Major, Felix; Schuberth, Ingrid; Spiegl, Dirk A.; Krewer, Birgit; Maksimenka, Katja; Bringmann, Gerhard; Magull, Jörg

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

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  • Medientyp: E-Artikel
  • Titel: Selective Treatment of Cancer: Synthesis, Biological Evaluation and Structural Elucidation of Novel Analogues of the Antibiotic CC‐1065 and the Duocarmycins
  • Beteiligte: Tietze, Lutz F.; Major, Felix; Schuberth, Ingrid; Spiegl, Dirk A.; Krewer, Birgit; Maksimenka, Katja; Bringmann, Gerhard; Magull, Jörg
  • Erschienen: Wiley, 2007
  • Erschienen in: Chemistry – A European Journal
  • Sprache: Englisch
  • DOI: 10.1002/chem.200700113
  • ISSN: 0947-6539; 1521-3765
  • Schlagwörter: General Chemistry ; Catalysis ; Organic Chemistry
  • Entstehung:
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  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>Novel diastereomerically pure β‐<jats:sc>D</jats:sc>‐galactosidic prodrugs (+)‐<jats:bold>12 a</jats:bold>–<jats:bold>e</jats:bold> of the cytotoxic antibiotics CC‐1065 and the duocarmycins were prepared for an antibody directed enzyme prodrug therapy (ADEPT) using <jats:bold>4</jats:bold> as a substrate via a radical cyclization to give <jats:italic>rac</jats:italic>‐<jats:bold>5</jats:bold> and <jats:italic>rac</jats:italic>‐<jats:bold>6</jats:bold> followed by a chromatographic resolution of the enantiomers of <jats:italic>rac</jats:italic>‐<jats:bold>5</jats:bold>, glycosidation and linkage to the DNA‐binding units <jats:bold>10 a</jats:bold>–<jats:bold>e</jats:bold>. These only slightly toxic compounds can be toxified enzymatically by an antibody–β‐<jats:sc>D</jats:sc>‐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 QIC<jats:sub>50</jats:sub> values of 4800 and 4300 for (+)‐<jats:bold>12 a</jats:bold> and (+)‐<jats:bold>12 b</jats:bold>, respectively. The absolute configuration of precursor (+)‐<jats:bold>5</jats:bold> was determined by comparison of the experimental CD spectrum with the theoretically predicted CD spectra and by X‐ray structure analysis.</jats:p>