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Modeling the Action of an Antitumor Drug: A Density Functional Theory Study of the Mechanism of Tirapazamine
journal contribution
posted on 2001-07-07, 00:00 authored by Fuqiang Ban, James W. Gauld, Russell J. BoydDensity functional theory methods are employed to investigate experimentally proposed mechanisms
by which the antitumor drug tirapazamine may react with a DNA sugar-C1‘ radical to give the sugar derivative
deoxyribonolactone, with concomitant DNA strand breakage. For the previously proposed minor pathway,
ionization of the sugar-C1‘ radical by tirapazamine, the calculated ionization energy, and the electron affinity
of the models of the sugar-C1‘ radical of DNA and tirapazamine suggest that tirapazamine must be protonated
to be able to oxidize the sugar-C1‘ radical. The preferred mechanism for reaction of tirapazamine with a sugar-C1‘ radical, in agreement with experimental observations, is found to proceed by direct attack of an N-oxide
oxygen of tirapazamine at the sugar-C1‘ position, followed by homolytic cleavage of the N−O bond of the
drug moiety. Possible alternative mechanisms are also investigated.