Structure of Adduct X, the Last Unknown of the Six Major DNA Adducts of Mitomycin C Formed in EMT6 Mouse Mammary Tumor Cells

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Abstract
Treatment of EMT6 mouse mammary tumor cells with mitomycin C (MC) results in the formation of six major MC−DNA adducts. We identified the last unknown of these (“adduct X”) as a guanine N2 adduct of 2,7-diaminomitosene (2,7-DAM), in which the mitosene is linked at its C-10 position to guanine N2. The assigned structure is based on UV and mass spectra of adduct X isolated directly from the cells, as well as on its difference UV, second-derivative UV, and circular dichroism spectra, synthesis from [8-3H]deoxyguanosine, and observation of its heat stability. These tests were carried out using 17 μg of synthetic material altogether. The mechanism of formation of adduct X involves reductive metabolism of MC to 2,7-DAM, which undergoes a second round of reductive activation to alkylate DNA, yielding adduct X and another 2,7-DAM−guanine adduct (adduct Y), which is linked at guanine N7 to the mitosene. Adduct Y has been described previously. Adduct X is formed preferentially at GpC, while adduct Y favors the GpG sequence. In contrast to MC−DNA adducts, the 2,7-DAM−DNA adducts are not cytotoxic.

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