Modeling the action of an antitumor drug: A density functional theory study of the mechanism of tirapazamine

Density functional theory methods are employed to investigate experimentall y proposed mechanisms by which the antitumor drug tirapazamine may react wi th a DNA sugar-C-1' radical to give the sugar derivative deoxyribonolactone , with concomitant DNA strand breakage. For the previously proposed minor p athway, ionization of the sugar-C-1' radical by tirapazamine, the calculate d ionization energy, and the electron affinity of the models of the sugar-C -1' radical of DNA and tirapazamine suggest that tirapazamine must be proto nated to be able to oxidize the sugar-C-1' radical. The preferred mechanism for reaction of tirapazamine with a sugar-C-1' radical, in agreement with experimental observations, is found to proceed by direct attack of an N-oxi de oxygen of tirapazamine at the sugar-C-1' position, followed by homolytic cleavage of the N-O bond of the drug moiety. Possible alternative mechanis ms are also investigated.