New 2-substituted indoloquinone mitomycin analogues

Previously reported 2-(hydroxymethyl)indoloquinones, prepared as their acetates or carbamates, were less active than 2-methyl analogues in bacterial cultures and they had no activity in mice, despite functionality appropriate for DNA cross-linking. On the basis of the hypothesis that these compounds might have been too reactive chemically for selective alkylation of DNA, we prepared new analogues with substituents that could give variation in the reduction potential of the quinone ring, which might control their rate of bioactivation. The 5-methoxyindoloquinones were much more potent cytotoxics than mitomycin C against human tumor cell lines, but they were inactive against P388 leukemia in mice. Two 5-aziridinylindoloquinones were also more potent than mitomycin C against the cell lines and one of them was active in the P388 model upon in vivo assay. The corresponding 5-amino analogues were less potent than mitomycin C against both the cell lines and murine P388 leukemia. A 2-(1-hydroxyethyl)carbamate was prepared by a 20-step synthesis. It was about one-fourth as potent as mitomycin C against two cell lines.