Tirapazamine (TPZ, 3-amino-1,2,4-benzotriazine 1,4-N-dioxide) can cause hypoxia-selective, redox-activated DNA strand cleavage and nucleobase damage in solid tumors.  Although actively studied for over two decades, the nature of the species responsible for DNA damage under hypoxia remains under investigation.  To elucidate the mechanism of TPZ activity and to improve its in vivo efficacy, a series of TPZ analogs were synthesized and studied in the Gates laboratory and possible reaction channels for their activation are being studied with modern electronic structure methods by the Glaser group. In the present work, higher-level correlated methods (QCI//DFT) were employed to investigate the homolytic fragmentation processes of TPZ analogs and to identify and characterize their major metabolites.  The new results suggest that the redox-activation mechanism of tirapazamine (X(C3) = NH2) also applies to the parent system (X = H) as well as the 3-methyl (X = CH3) and 3-cyclopropyl (X = C3H5) analogs.  On the other hand and in agreement with experimental observations, the PES analysis of 3-amino-2-quinoxalinecarbonitrile 1,4-di-N-oxide shows a reversal of the regiochemical preference of N-OH homolysis as compared to TPZ.

QCI//DFT studies of heterocyclic di-N-oxides with antitumor activity: Mechanistic insights from tirapazamine analogs

243rd National Meeting (2012)

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