Netzeva Tatiana I, Schultz T Wayne
European Chemicals Bureau (ECB), Institute for Health and Consumer Protection, Joint Research Centre, 21020 Ispra (VA), Italy.
Chemosphere. 2005 Dec;61(11):1632-43. doi: 10.1016/j.chemosphere.2005.04.040. Epub 2005 Jun 13.
The aim of the study was to develop quantitative structure-activity relationships (QSARs) for a large group of 77 aromatic aldehydes tested for acute toxicity to the ciliate Tetrahymena pyriformis using mechanistically interpretable descriptors. The resulting QSARs revealed that the 1-octanol/water partition coefficient (log K(ow)), is the most important descriptor of aldehyde aquatic toxic potency. The model with log K(ow) was improved by adding electronic descriptor (the maximum acceptor superdelocalizability in a molecule--A(max)) based on calculations with the semi-empirical AM1 model. The two descriptors reflect the two main processes responsible for demonstration of acute aquatic toxicity, namely penetration through cell membranes (log K(ow)) and interaction with the biomacromolecules (A(max)) into the cells. Results showed that generally the studied group of aldehydes could be modeled by this simple two-descriptor approach. However, the group of 2- and/or 4-hydroxylated aldehydes demonstrates enhanced toxicity compared to the other aldehydes. Transformation to quinone-like structures is proposed as the explanation for this enhanced potency. The 2- and/or 4-hydroxylated aldehydes are modeled successfully by [log(1/IGC50) = 0.540(0.038) log K(ow) + 8.30(2.88)A(max) - 3.11(0.92), n = 25, R2 = 0.916, R(CV)2 = 0.896, s = 0.141, F = 120], while the other aldehydes are modeled by the relationship [log(1/IGC50) = 0.583 (0.034)log K(ow) + 9.80(2.62)A(max) - 4.04 (0.85), n = 52, R2 = 0.864, R(CV)2 = 0.844, s = 0.203, F = 156], which is similar to the general benzene model.
本研究的目的是使用可进行机理解释的描述符，针对一大组77种芳香醛对梨形四膜虫的急性毒性建立定量构效关系（QSAR）。所得的QSAR表明，正辛醇/水分配系数（log K(ow)）是醛类水生毒性效力的最重要描述符。通过基于半经验AM1模型的计算添加电子描述符（分子中的最大受体超离域化——A(max)），改进了包含log K(ow)的模型。这两个描述符反映了造成急性水生毒性的两个主要过程，即穿过细胞膜（log K(ow)）以及与生物大分子（A(max)）相互作用进入细胞。结果表明，一般来说，所研究的醛类组可以用这种简单的双描述符方法进行建模。然而，2-和/或4-羟基化醛类组相较于其他醛类表现出更高的毒性。有人提出转化为醌样结构是这种增强效力的解释。2-和/或4-羟基化醛类通过[log(1/IGC50) = 0.540(0.038) log K(ow) + 8.30(2.88)A(max) - 3.11(0.92)，n = 25，R2 = 0.916，R(CV)2 = 0.896，s = 0.141，F = 120]成功建模，而其他醛类则通过[log(1/IGC50) = 0.583 (0.034)log K(ow) + 9.80(2.62)A(max) - 4.04 (0.85)，n = 52，R2 = 0.864，R(CV)2 = 0.844，s = 0.203，F = 156]进行建模，该关系与一般的苯模型相似。
