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-.alpha.] 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.
