Electron and Spin-Density Analysis of Tirapazamine Reduction Chemistry


Tirapazamine (TPZ, 1, 3-amino-1,2,4-benzotriazine 1,4-N,N-dioxide), the radical anion 2 formed by one-electron reduction of 1, and neutral radicals 3 and 4 formed by protonation of 2 at O(N4) or O(N1), respectively, and their N-OH homolyses 3 → 5 + ·OH and 4 → 6 + ·OH have been studied with configuration interaction theory, perturbation theory, and density functional theory. A comprehensive comparative analysis is presented of structures and electronic structures and with focus on the development of an understanding of the spin-density distributions of the radical species. The skeletons of radicals 3 and 4 are distinctly nonplanar, several stereoisomeric structures are discussed, and there exists an intrinsic preference for 3 over 4. The N-oxides 1, 5, and 6 have closed-shell singlet ground states and low-lying, singlet biradical (SP-1, SP-6) or biradicaloid (SP-5) excited states. The doublet radicals 2, 3, and 4 are heavily spin-polarized. Most of the spin density of the doublet radicals 2, 3, and 4 is located in one (N,O)-region, and in particular, 3 and 4 are not C3-centered radicals. Significant amounts of spin density occur in both rings in the singlet biradical(oid) excited states of 1, 5, and 6. The dipole moment of the N2-C3(X) bond is large, and the nature of X provides a powerful handle to modulate the N2-C3 bond polarity with opposite effects on the two NO regions. Our studies show very low proton affinities of radical anion 2 and suggest that the pKa of radical [2+H] might be lower than 6. Implications are discussed regarding the formation of hydroxyl from 3 and/or 4, regarding the ability of 5 and 6 to react with carbon-centered radicals in a manner that ultimately leads to oxygen transfer, and regarding the interpretation of the EPR spectra of reduced TPZ species and of their spin-trap adducts.



Keywords and Phrases

anion; groups with a carbon-nitrogen bond only; hydroxyl group; proton; radical; tirapazamine; binding affinity; chemical bond; density functional theory; dipole; electron; pKa; proton transport; reduction kinetics; stereoisomerism; Antineoplastic Agents; Electrons; Models; Chemical; 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