On the Reaction Mechanism of Tirapazamine Reduction Chemistry: Unimolecular N-OH Homolysis, Stepwise Dehydration, or Triazene Ring-Opening


The initial steps of the activation of tirapazamine (TPZ, 1, 3-amino-1,2,4-benzotriazine 1,4-N,N-dioxide) under hypoxic conditions consist of the one-electron reduction of 1 to radical anion 2 and the protonation of 2 at O(N4) or O(N1) to form neutral radicals 3 and 4, respectively. There are some questions, however, as to whether radicals 3 and/or 4 will then undergo N-OH homolyses 35 + ·OH and 46 + ·OH or, alternatively, whether 3 and/or 4 may react by dehydration and form aminyl radicals via 311 + H2O and 412 + H2O or phenyl radicals via 317 + H2O. These outcomes might depend on the chemistry after the homolysis of 3 and/or 4, that is, dehydration may be the result of a two-step sequence that involves N-OH homolysis and formation of ·OH aggregates of 5 and 6 followed by H-abstraction within the ·OH aggregates to form hydrates of aminyls 11 and 12 or of phenyl 17. We studied these processes with configuration interaction theory, perturbation theory, and density functional theory. All stationary structures of OH aggregates of 5 and 6, of H2O aggregates of 11, 12, and 17, and of the transition state structures for H-abstraction were located and characterized by vibrational analysis and with methods of electron and spin-density analysis. The doublet radical 17 is a normal spin-polarized radical, whereas the doublet radicals 11 and 12 feature quartet instabilities. The computed reaction energies and activation barriers allow for dehydration in principle, but the productivity of all of these channels should be low for kinetic and dynamic reasons. With a view to plausible scenarios for the generation of latent aryl radical species without dehydration, we scanned the potential energy surfaces of 2-4 as a function of the (O)N1-Y (Y = C5a, N2) and (O)N4-Z (Z = C4a, C3) bond lengths. The elongation of any one of these bonds by 0.5 Å requires less than 25 kcal/mol, and this finding strongly suggests the possibility of bimolecular reactions of the spin-trap molecules with 2-4 concomitant with triazene ring-opening.



Keywords and Phrases

anion; hydroxyl group; phenyl group; radical; tirapazamine; triazene derivative; water; chemical bond; dehydration; density functional theory; electron; hypoxia; proton transport; reaction analysis; reduction; reduction kinetics; ring opening; Antineoplastic Agents; Desiccation; Hydroxyl Radical; Nitrogen; Oxidation-Reduction; Spin Trapping; Triazines

International Standard Serial Number (ISSN)

0893-228X; 1520-5010

Document Type

Article - Journal

Document Version


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© 2012 American Chemical Society (ACS), All rights reserved.

Publication Date

01 Mar 2012