Mekenyan O, Roberts D W, Karcher W
Bourgas University Ass. Zlataro, Bulgaria.
Chem Res Toxicol. 1997 Sep;10(9):994-1000. doi: 10.1021/tx960104g.
The electrophilic reactivity of a training set of 20 halo- and pseudohalobenzenes, 10 of which are reported skin sensitizers and 10 of which are reported nonsensitizers, has been modeled by MO-calculated indices using the AM1 and PM3 Hamiltonians. The electronic structures of parent molecules and the corresponding Meisenheimer intermediates (sigma-complexes) were evaluated. The NH2 group and the H atom were both studied as model nucleophile-derived substituents in the sigma-complexes. The LUMO energy differences between the parent compounds and their Meisenheimer complexes together with the maximum acceptor superdelocalizabilities determined over the aromatic reaction sites were found to discriminate correctly the sensitizing/reactive from nonsensitizing/unreactive compounds of the training set of 20 compounds. The predictive applicability of these MO indices was confirmed with a test set of seven further compounds for which sensitization data are reported in the literature. A statistically based discriminant analysis provides a model which predicts whether or not an SNAr electrophile will be a sensitizer and estimates the degree of confidence in the prediction.
采用AM1和PM3哈密顿量，通过分子轨道（MO）计算指数对一组包含20种卤代苯和拟卤代苯的训练集进行亲电反应性建模，其中10种被报道为皮肤致敏剂，10种被报道为非致敏剂。评估了母体分子及其相应的迈森海默中间体（σ-络合物）的电子结构。在σ-络合物中，NH₂基团和H原子均作为模型亲核试剂衍生的取代基进行了研究。母体化合物与其迈森海默络合物之间的最低未占分子轨道（LUMO）能量差，以及在芳香族反应位点上确定的最大受体超离域性，能够正确区分训练集中20种化合物的致敏/反应性化合物与非致敏/非反应性化合物。文献中报道了另外七种化合物的致敏数据，以此测试集证实了这些MO指数的预测适用性。基于统计的判别分析提供了一个模型，该模型可预测亲核芳香取代（SNAr）亲电试剂是否会成为致敏剂，并估计预测的置信度。
