Colvin M E, Seidl E T, Nielsen I M, Le Bui L, Hatch F T
Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermmore, CA 94550, USA.
Chem Biol Interact. 1997 Dec 12;108(1-2):39-66. doi: 10.1016/s0009-2797(97)00094-x.
The mutagenicity of many 2-aminoimidazole-azaarenes (AIA) is thought to be mediated by the nitrenium form of the exocyclic amine. This hypothesis is supported by the numerous correlations found between calculated and experimentally-measured chemical properties for the nitreniums and the mutagenic potencies of the nitreniums and their parent amines. One factor favoring high mutagenic potency is the presence of a methyl substituent in the 1- or 3-imidazole position. In this paper, we investigate both the deprotonation of the imidazole ring nitrogens in non-N-methylated AIA mutagens and the plausibility of a chemical pathway involving a 1-4 hydride shift to form an iminium ion, thereby stabilizing the cationic N-methyl substituted AIA mutagens. It has been widely noted that factors that stabilize the nitrenium moiety lead to significantly higher mutagenic potency; hence, the transformation of the nitrenium to a more stable species might be expected to increase the potency, provided that it does not eliminate the electrophilic reactivity of the compound. Using ab initio quantum chemistry and polarizable continuum solvation models, we find that the imidazole ring nitrogens of the nitrenium ions are extremely acidic. This suggests that upon formation of the exocyclic nitrenium these sites will deprotonate to form a neutral imine. We have also studied the 1-4 hydride shift from an imidazole ring methyl to the exocyclic nitrenium to form an iminium. We predict that for AIA mutagens with just two fused rings the resulting iminium species are more stable in the gas phase than the corresponding nitreniums. For mutagens with larger conjugated systems, the nitrenium is stabilized by resonance and is more stable than the corresponding iminium. In the aqueous phase, however, the iminium form is predicted to be more stable than the nitreniums for all polycyclic compounds studied. Although equilibrium calculations favor the iminium form, these have been experimentally shown to be short-lived and their actual concentration will depend on the complex kinetics of AIA mutagen metabolism. The quantum chemical results also show a strong correlation between the relative iminium-nitrenium energy difference and the charge on the exocyclic nitrogen.
许多2-氨基咪唑氮杂芳烃（AIA）的致突变性被认为是由环外胺的氮宾形式介导的。这一假设得到了氮宾的计算化学性质与实验测量化学性质之间以及氮宾及其母体胺的致突变潜能之间众多相关性的支持。有利于高致突变潜能的一个因素是在1-或3-咪唑位置存在甲基取代基。在本文中，我们研究了非N-甲基化AIA诱变剂中咪唑环氮的去质子化以及涉及1,4-氢迁移以形成亚胺离子从而稳定阳离子N-甲基取代AIA诱变剂的化学途径的合理性。人们普遍注意到，稳定氮宾部分的因素会导致显著更高的致突变潜能；因此，如果不消除化合物的亲电反应性，预计氮宾向更稳定物种的转化会增加其潜能。使用从头算量子化学和极化连续介质溶剂化模型，我们发现氮宾离子的咪唑环氮极具酸性。这表明在形成环外氮宾时，这些位点将去质子化形成中性亚胺。我们还研究了从咪唑环甲基到环外氮宾的1,4-氢迁移以形成亚胺离子。我们预测，对于只有两个稠合环的AIA诱变剂，生成的亚胺物种在气相中比相应的氮宾更稳定。对于具有更大共轭体系的诱变剂，氮宾通过共振得到稳定，比相应的亚胺更稳定。然而，在水相中，对于所有研究的多环化合物，预计亚胺形式比氮宾更稳定。尽管平衡计算有利于亚胺形式，但实验表明它们寿命短暂，其实际浓度将取决于AIA诱变剂代谢的复杂动力学。量子化学结果还表明亚胺-氮宾相对能量差与环外氮上的电荷之间存在很强的相关性。
