Structural and function modification of DNA by mitomycin C. Mechanism of the DNA sequence specificity of mitomycins

Mitomycin C (MC) is a clinically used antitumor agent, which upon reductive activation activates and cross-links DNA. The covalent products of alkylation and cross-linking by the unnatural synthetic enantiomer of MC (ent-MC) were isolated as drug-deoxyguanosine monoadducts and drug-deoxyguanosine bisadducts and were fully characterized structurally. Specificity of alkylation and cross-linking of guanines in the CpG.CpG sequence was observed by ent-MC, similarly to that observed previously by MC. These findings define the mechanism of recognition of the CpG.CpG sequence of DNA by the mitomycins in the minor groove. In contrast, the natural MC metabolite, 2,7-diaminomitosene (2,7-DAM) which lacks the aziridine alkylator function is shown to recognize and alkylate guanines only the GpG.CpC sequence in the major groove, by a different mechanism. Thoughts on the molecular evolution of the basic mitomycin structure as a very efficient lethal DNA cross-linker are discussed.