Das hypoxämische Ziel im Blick: Die Kombination einer Nitro‐Wirkstoffvorstufe mit einem wasserlöslichen Phosphat wandelt Duocarmycin‐Analoga von hoch toxischen DNA‐Alkylierungsmitteln in hoch selektive Tumorwirkstoffe um. Diese Wirkstoffvorstufen (siehe Schema) sind in vivo außergewöhnlich wirksam gegen hypoxämische Tumorzellen – die Zellen, die allgemein als am schlechtesten durch herkömmliche Therapiemethoden erreichbar gelten.

Nitrochloromethylbenzindolines (nitroCBIs) are a new class of hypoxia-activated prodrugs for antitumor therapy. The recently reported prototypes undergo hypoxia-selective metabolism to form potent DNA minor groove alkylating agents and are selectively toxic to some but not all hypoxic tumor cell lines. Here we report a series of 31 analogues that bear an extra electron-withdrawing substituent that serves to raise the one-electron reduction potential of the nitroCBI. We identify a subset of compounds, those with a basic side chain and sulfonamide or carboxamide substituent, that have consistently high hypoxic selectivity. The best of these, with a 7-sulfonamide substituent, displays hypoxic cytotoxicity ratios of 275 and 330 in Skov3 and HT29 human tumor cell lines, respectively. This compound (28) is efficiently and selectively metabolized to the corresponding aminoCBI, is selectively cytotoxic under hypoxia in all 11 cell lines examined, and demonstrates activity against hypoxic tumor cells in a human tumor xenograft in vivo.

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