title: Electron and spin-density analysis of tirapazamine reduction chemistry.
abstract: 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 pK(a) 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.
authors.affiliation: Department of Chemistry, University of Missouri, Columbia, Missouri 65211, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Yin
authors.forename: Rainer
authors.initials: R
authors.lastname: Glaser
authors.forename: Kent S
authors.initials: KS
authors.lastname: Gates
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D004583:Electrons; D008956:Models, Chemical; D010084:Oxidation-Reduction; D019097:Spin Trapping; D000077704:Tirapazamine; D014227:Triazines / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D014227:Triazines; D000077704:Tirapazamine