Mayr H, Ofial A R
a Department Chemie der Ludwig-Maximilians-Universität München , München , Germany.
SAR QSAR Environ Res. 2015;26(7-9):619-46. doi: 10.1080/1062936X.2015.1078409. Epub 2015 Aug 28.
A method is presented which allows one to predict toxic effects which are triggered by the formation of covalent bonds between electron-deficient (electrophilic) compounds and biological electron-rich (nucleophilic) targets, as proteins or nucleic acids. It is based on our comprehensive nucleophilicity and electrophilicity scales, which we constructed as an aid for the planning of organic syntheses. For the construction of these scales, rate constants for the reactions of benzhydrylium ions (aryl2CH(+)) and structurally related quinone methides with nucleophiles have been measured and correlated by the equation lg k(20 °C) = sN(E + N), which yields absolute rate constants k (L mol(-1) s(-1)) from one parameter for electrophiles (the electrophilicity E) and two for nucleophiles (the nucleophilicity parameter N and the susceptibility sN). A freely accessible database (http://www.cup.uni-muenchen.de/oc/mayr/DBintro.html) is described, which presently comprises data for 1000 nucleophiles and 260 electrophiles and provides links to the original literature reports. The kinetic scales are complemented by a thermodynamic counterpart, which enables one to calculate association constants K (L mol(-1)) of electrophiles with nucleophiles from the empirical Lewis acidity parameters LA and Lewis basicity parameters LB by the equation lg K (20°C) = LA + LB.
本文提出了一种方法，该方法能够预测因缺电子（亲电）化合物与生物富电子（亲核）靶点（如蛋白质或核酸）之间形成共价键而引发的毒性效应。该方法基于我们构建的综合亲核性和亲电性标度，这些标度是为辅助有机合成规划而构建的。为构建这些标度，已测量了二苯甲基正离子（芳基₂CH⁺）和结构相关的醌甲基化物与亲核试剂反应的速率常数，并通过方程lg k(20 °C) = sN(E + N)进行关联，该方程从一个亲电试剂参数（亲电性E）和两个亲核试剂参数（亲核性参数N和敏感性sN）得出绝对速率常数k（L·mol⁻¹·s⁻¹）。文中描述了一个可免费访问的数据库（http://www.cup.uni-muenchen.de/oc/mayr/DBintro.html），该数据库目前包含1000种亲核试剂和260种亲电试剂的数据，并提供了与原始文献报告的链接。动力学标度由一个热力学对应物补充，通过方程lg K (20°C) = LA + LB，该对应物能够根据经验性的路易斯酸度参数LA和路易斯碱度参数LB计算亲电试剂与亲核试剂的缔合常数K（L·mol⁻¹）。
