Hatch F T, Colvin M E, Seidl E T
Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermore, California, USA.
Environ Mol Mutagen. 1996;27(4):314-30. doi: 10.1002/(SICI)1098-2280(1996)27:4<314::AID-EM6>3.0.CO;2-C.
A set of 16 mutagenic aminoimidazo-azaarenes, including four that have been isolated from cooked foods and identified as bacterial mutagens and rodent carcinogens, was selected from a larger series previously published [Hatch et al. (1991): Environ Mol Mutagen 17:4-19] for an in-depth structure-activity study using computational methods. Structural features believed to affect mutagenic potency were tabulated. Molecular orbital energies and other electronic properties of these compounds were calculated using Huckel, semiempirical AM1, and ab initio quantum mechanical methods. Factor interrelationships were studied by multiple linear regression and canonical correlation analyses. Our goal was an improved understanding of the chemical basis of mutagenicity for this class of heterocyclic amines. The major findings were as follows: 1) mutagenic potency is related to the size of the aromatic ring system; 2) potency is enhanced by the presence and location of an N-methyl group; 3) potency is enhanced by addition of ring nitrogen atoms in pyridine, quinoline, and quinoxaline configurations; 4) potency is inversely related to the energy of the LUMO (lowest unoccupied molecular orbital) of the parent amines; 5) potency is directly, though weakly, related to the LUMO energy of the derived nitrenium ions; and 6) the calculated thermodynamic stability of the nitrenium ions (relative to the parent amine) is directly correlated with nitrenium LUMO energy and with the negative charge on the exocyclic nitrogen atom. Although this study raises several intriguing issues relating mutagenicity to chemical properties, further study will be required to determine the plausibility of the nitrenium ion as the ultimate mutagen for binding to DNA.
从先前发表的较大系列中[哈奇等人（1991年）：《环境与分子诱变》17:4 - 19]选取了一组16种诱变氨基咪唑 - 氮杂芳烃，其中包括4种已从熟食中分离出来并被鉴定为细菌诱变剂和啮齿动物致癌物的物质，用于使用计算方法进行深入的构效关系研究。列出了被认为影响诱变效力的结构特征。使用休克尔方法、半经验AM1方法和从头算量子力学方法计算了这些化合物的分子轨道能量和其他电子性质。通过多元线性回归和典型相关分析研究了因素间的相互关系。我们的目标是更好地理解这类杂环胺致突变性的化学基础。主要发现如下：1）诱变效力与芳环系统的大小有关；2）N - 甲基的存在和位置会增强效力；3）吡啶、喹啉和喹喔啉构型中添加环氮原子会增强效力；4）效力与母体胺的最低未占分子轨道（LUMO）能量呈反比；5）效力与衍生的氮鎓离子的LUMO能量直接相关，尽管相关性较弱；6）计算得出的氮鎓离子（相对于母体胺）的热力学稳定性与氮鎓LUMO能量以及环外氮原子上的负电荷直接相关。尽管这项研究提出了几个将致突变性与化学性质相关联的有趣问题，但仍需要进一步研究来确定氮鎓离子作为与DNA结合的最终诱变剂的合理性。
