DNA adduct formation of mitomycin C. A test case for DFT calculations on model systems

Mitomycin C is a DNA alkylating agent activated by bioreduction. It has been in clinical use against a range of solid tumours since the 1960s. Its DNA adduct formation mechanism has been extensively studied and it therefore presents an excellent test case for the applicability of Density Functional Theory (DFT) calculations based on simple model systems. The reaction cascades proposed in the literature were calculated and the results revealed that many of the mechanistic features were correctly predicted: the one- and two-electron reduction was deemed plausible, the pH-dependence of the rate of aziridine ring opening, and that the alkylating agent is required to be formed in the proximity of DNA for adduct formation to occur. The DFT method was unable to predict where adduct formation takes place on the guanine based on the exothermicity of the nucleophilic attack. Overall, the DFT method does well to predict the mechanism for adduct formation considering that the model systems are simple and modest CPU requirements.