The Reactions of Mitomycin C with Dithiols II. Formation of Dithiol Cross-Links

We report that the clinically used antitumor drug mitomycin C reacts with excess dithiols to give dithiol cross-links as major products. Mechanistic studies reveal that three dithiol molecules participate at different stages of the reaction: in the reductive activation of mitomyicin C, in an alkylation at C1, and in an additional reduction that activates C10 for the second-arm alkylation by the dithiol. We hypothesize that the reactions reported here indicate that mitomycin C could act as a mechanism-based inhibitor of enzymes containing a dithiol active site.