Cytotoxic N-unsubstituted indoles and cyclopent(b)indoles and method of making and using same

Abstract

The merits of N-unsubstituted indoles and cyclopent[b]indoles as DNA-directed reductive alkylating agents are described. These systems represent a significant departure from N-substituted and pyrrolo[1,2-a] fused systems such as the mitomycins and mitosenes. The cyclopent[b]indole—based aziridinylquinone, when bearing an acetate leaving group, was found to be cytotoxic and displayed significant in vivo activity against syngeneic tumor implants. This particular analogue was unexpectedly superior to the others studied, both in terms of high specificity for the activating enzyme DT-diaphorase and in high % DNA alkylation. Alkylation by a quinone methide intermediate as well as by the aziridinyl group were examined for crosslinking. The possible metabolites of the most active indole species were prepared and found to retain cytotoxicity, strongly suggesting that in vivo activity could also be sustained. The indole systems in the present invention display selectivity for melanoma and for non small cell lung, colon, renal, and prostate cancers when administered in an effective amount. The cancer specificity observed is believed to pertain to differential substrate specificity for DT-diaphorase.

Dependencies are inferred from the claim text.