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 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.
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Contribution from the Department of Chemistry, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4J3.
Gauld
J W
JW
Boyd
R J
RJ
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D008962:Models, Theoretical; D010084:Oxidation-Reduction; D000077704:Tirapazamine; D014227:Triazines / Q000737:chemistry* / Q000494:pharmacology*
D000970:Antineoplastic Agents; D014227:Triazines; D000077704:Tirapazamine