Cronin M T, Manga N, Seward J R, Sinks G D, Schultz T W
School of Pharmacy and Chemistry, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, England.
Chem Res Toxicol. 2001 Nov;14(11):1498-505. doi: 10.1021/tx015502k.
The aim of this study was to determine which descriptor best parametrized the electrophilicity of aromatic compounds with regard to their acute toxicity. To achieve this, toxicity data for 203 substituted aromatic compounds containing a nitro- or cyano group were evaluated in the 40-h Tetrahymena pyriformis population growth impairment assay. Quantitative structure-activity relationships (QSARs) were developed relating toxic potency [log(IGC(50)(-1))] with hydrophobicity quantified by the 1-octanol/water partition coefficient (log P) and electrophilic reactivity quantified by the molecular orbital parameters, either the energy of the lowest unoccupied molecular orbital (E(LUMO)) or maximum acceptor superdelocalizability (A(max)) was developed. For the full data set, E(LUMO) and A(max) were collinear (r = 0.87). A comparison of the QSARs [log(IGC(50)(-1)) = 0.40 log P - 0.94E(LUMO) - 1.27; n = 203, r(2) = 0.60, s = 0.49, F = 151] and [log(IGC(50)(-1)) = 0.37 log P + 13.1A(max) - 4.30; n = 203, r(2) = 0.70, s = 0.42, F = 237] reveals A(max) to be the better electrophilic parameter for modeling these data. Analysis of outliers indicates a preponderance of 4-subsituted nitrophenols and nitroanilines. Smaller datasets (51 and 102 compounds) selected in order to reduce the collinearity between A(max) and E(LUMO) were also evaluated. Results indicate A(max) to be the superior descriptor of electrophilicity for the purpose of toxicological QSARs for aromatic compounds. Development of QSARs using partial least-squares yielded similar results.
本研究的目的是确定在芳香族化合物的急性毒性方面，哪种描述符能最好地参数化其亲电性。为实现这一目标，在40小时梨形四膜虫种群生长抑制试验中评估了203种含硝基或氰基的取代芳香族化合物的毒性数据。建立了定量构效关系（QSARs），将毒性效力[log(IGC(50)(-1))]与通过1-辛醇/水分配系数（log P）量化的疏水性以及通过分子轨道参数量化的亲电反应性相关联，分子轨道参数可以是最低未占分子轨道的能量（E(LUMO)）或最大受体超离域性（A(max)）。对于完整数据集，E(LUMO)和A(max)是共线关系（r = 0.87）。对QSARs [log(IGC(50)(-1)) = 0.40 log P - 0.94E(LUMO) - 1.27；n = 203，r(2) = 0.60，s = 0.49，F = 151] 和 [log(IGC(50)(-1)) = 0.37 log P + 13.1A(max) - 4.30；n = 203，r(2) = 0.70，s = 0.42，F = 237] 的比较表明，A(max)是对这些数据进行建模的更好的亲电参数。异常值分析表明主要是4-取代硝基苯酚和硝基苯胺。为了降低A(max)和E(LUMO)之间的共线性而选择的较小数据集（51种和102种化合物）也进行了评估。结果表明，对于芳香族化合物的毒理学QSARs而言，A(max)是亲电性的更优描述符。使用偏最小二乘法建立QSARs也得到了类似结果。
