Inhibition of carboxylesterases by benzil (diphenylethane-1,2-dione) and heterocyclic analogues is dependent upon the aromaticity of the ring and the flexibility of the dione moiety
Inhibition of carboxylesterases by benzil (diphenylethane-1,2-dione) and heterocyclic analogues is dependent upon the aromaticity of the ring and the flexibility of the dione moiety
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DOI：
10.1021/jm0504196
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发表时间：
2005-08-25
影响因子：
7.3
通讯作者：
Potter, PM
中科院分区：
文献类型：
--
作者：
Hyatt, JL;Stacy, V;Potter, PM
苯偶酰是一种选择性的羧酸酯酶抑制剂。抑制活性所需的分子的基本组分包括二酮部分和苯环，并且环内的取代提供对来自不同物种的CE的增加的选择性。用杂环取代基取代苯环增加了化合物的Ki值，当使用邻硝基苯乙酸酯作为底物时，其朝向三种哺乳动物CE。Ki值与经验共振能、形成能的结合热或从环结构的分子轨道计算确定的芳族稳定能的对数图产生线性关系，其允许预测二酮对CE抑制的功效。利用这些数据，我们预测2，2 '-萘酚将是哺乳动物CE的优良抑制剂。这被证明是正确的，在兔肝CE中观察到的Ki值为1 nM。此外，分子模拟的环结构周围的二酮二面角的运动表明，该化合物的能力，以抑制CE是由于，在一定程度上，由二酮部分强制执行的旋转约束。总体而言，这些研究确定了负责CE抑制的芳香族乙烷-1，2-二酮内的亚结构域。
Benzil has been identified as a potent selective inhibitor of carboxylesterases (CEs). Essential components of the molecule required for inhibitory activity include the dione moiety and the benzene rings, and substitution within the rings affords increased selectivity toward CEs from different species. Replacement of the benzene rings with heterocyclic substituents increased the K-i values for the compounds toward three mammalian CEs when using o-nitrophenyl acetate as a substrate. Logarithmic plots of the K-i values versus the empirical resonance energy, the heat of union of formation energy, or the aromatic stabilization energy determined from molecular orbital calculations for the ring structures yielded linear relationships that allowed prediction of the efficacy of the diones toward CE inhibition. Using these data, we predicted that 2,2'-naphthil would be an excellent inhibitor of mammalian CEs. This was demonstrated to be correct with a K-i value of 1 nM being observed for a rabbit liver CE. In addition, molecular simulations of the movement of the ring structures around the dione dihedral indicated that the ability of the compounds to inhibit CEs was due, in part, to rotational constraints enforced by the dione moiety. Overall, these studies identify subdomains within the aromatic ethane-1,2-diones, that are responsible for CE inhibition.