Design of cancer-specific antitumor agents based on aziridlinylcyclopent[b]indoloquinones

The merits of N-unsubstituted indoles and cyclopent[b]indoles as DNA-direct ed reductive alkylating agents are described. These systems represent a dep arture from N-substituted and pyrrolo[1,2-a]-fused systems such as the mito mycins and mitosenes. The cyclopent[b]indole-based aziridinylquinone system , when bearing an acetate leaving group with or without an N-acetyl group, was cytotoxic and displayed significant in vivo activity against syngeneic tumor implants. These analogues were superior to the others studied in term s of both high specificity for the activating enzyme DT-diaphorase and high percent DNA alkylation. Alkylation by a quinone methide intermediate as we ll as by the aziridinyl group could lead to cross-linking. The possible met abolites of the most active indole species were prepared and found to retai n cytotoxicity, suggesting that in vivo activity could be sustained. The in dole systems in the present study display selectivity for melanoma and, dep ending on the substituents present, selectivity for non-small-cell lung, co lon, renal, and prostate cancers. The cancer specificities observed are bel ieved to pertain to differential substrate specificities for DT-diaphorase.