Dimeric
DNA cross-linking compounds have emerged as important new
antitumor agents. We report the synthesis and biochemical evaluation of a select set of dimeric
mitomycins in which the two
mitomycin units are tethered at either the
mitomycin C(7) amino or the
aziridine N(1a) positions. Significantly,
mitomycin C (1) itself is the prototypical bioreductive
DNA cross-linking agent.
DNA cross-linking experiments using a denaturing-gel-electrophoresis-based assay showed that the extent of
DNA cross-linking for select dimeric
mitomycins can exceed that of the parent compound,
mitomycin C, and that the reaction proceeds, in part, at the two distal C(1) sites in the
mitomycins. The efficiency of
DNA cross-linking depended on the nature of the linker and the position of linker unit's attachment. When we compared the efficiency of
DNA cross-linking for the dimeric
mitomycins with their in vitro cytotoxicities in cultured human
tumor cells, we observed a poor correlation. The
mitomycins that gave the highest levels of
DNA cross-linked adducts displayed the weakest cytotoxicities. These findings determined that the denaturing-gel-electrophoresis-based assay was a poor predictor of cytotoxic activity.