title: Modeling the action of an antitumor drug: a density functional theory study of the mechanism of tirapazamine.
abstract: Density functional theory methods are employed to investigate experimentally proposed mechanisms by which the antitumor drug tirapazamine may react with a DNA sugar-C(1)' radical to give the sugar derivative deoxyribonolactone, with concomitant DNA strand breakage. For the previously proposed minor pathway, ionization of the sugar-C(1)' radical by tirapazamine, the calculated ionization energy, and the electron affinity of the models of the sugar-C(1)' radical of DNA and tirapazamine suggest that tirapazamine must be protonated 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-oxide oxygen of tirapazamine at the sugar-C(1)' position, followed by homolytic cleavage of the N-O bond of the drug moiety. Possible alternative mechanisms are also investigated.
authors.affiliation: Contribution from the Department of Chemistry, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4J3.
authors.forename: F
authors.initials: F
authors.lastname: Ban
authors.forename: J W
authors.initials: JW
authors.lastname: Gauld
authors.forename: R J
authors.initials: RJ
authors.lastname: Boyd
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D008962:Models, Theoretical; D010084:Oxidation-Reduction; D000077704:Tirapazamine; D014227:Triazines / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D014227:Triazines; D000077704:Tirapazamine