Department of Chemistry, University of Missouri, Columbia, Missouri 65211, USA.
Chem Res Toxicol. 2012 Mar 19;25(3):634-45. doi: 10.1021/tx200546u. Epub 2012 Mar 5.
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 3 → 5 + ·OH and 4 → 6 + ·OH or, alternatively, whether 3 and/or 4 may react by dehydration and form aminyl radicals via 3 → 11 + H(2)O and 4 → 12 + H(2)O or phenyl radicals via 3 → 17 + H(2)O. 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 H(2)O 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.
替拉扎胺（TPZ，1,3-氨基-1,2,4-苯并三嗪 1,4-N,N-二氧化物）在缺氧条件下的激活的初始步骤包括一电子还原 1 为自由基阴离子 2，以及 2 在 O(N4)或 O(N1)处质子化形成中性自由基 3 和 4。然而，存在一些问题，即自由基 3 和/或 4 是否会随后经历 N-OH 均裂 3 → 5 + ·OH 和 4 → 6 + ·OH，或者 3 和/或 4 是否可能通过脱水反应形成通过 3 → 11 + H(2)O 和 4 → 12 + H(2)O 形成氨自由基，或者通过 3 → 17 + H(2)O 形成苯自由基。这些结果可能取决于 3 和/或 4 的均裂后的化学，即脱水可能是两步序列的结果，该序列涉及 N-OH 均裂和形成·OH 聚合体 5 和 6，随后在·OH 聚合体中进行 H 提取，以形成氨 11 和 12 的水合物或苯 17 的水合物。我们使用组态相互作用理论、微扰理论和密度泛函理论研究了这些过程。通过振动分析和电子和自旋密度分析方法，定位并表征了 5 和 6 的·OH 聚合体、11、12 和 17 的 H(2)O 聚合体以及 H 提取的过渡态结构的所有稳定结构。自由基 17 是一个正常的自旋极化自由基，而自由基 11 和 12 则具有四重不稳定。计算的反应能量和活化能允许在原则上进行脱水，但由于动力学和动态原因，所有这些通道的产率都应该很低。为了寻找没有脱水的潜在芳基自由基生成的合理方案，我们作为（O）N1-Y（Y = C5a，N2）和（O）N4-Z（Z = C4a，C3）键长的函数扫描了 2-4 的势能表面。这些键中的任何一个键的伸长 0.5 Å 需要小于 25 kcal/mol，这一发现强烈表明自旋捕获分子与 2-4 的双分子反应同时伴随着三嗪环的打开的可能性。
