Selective inhibition of carboxylesterases by isatins, indole-2,3-diones
Selective inhibition of carboxylesterases by isatins, indole-2,3-diones
复制标题
DOI：
10.1021/jm061471k
复制
发表时间：
2007-04-19
影响因子：
7.3
通讯作者：
Potter, Philip M.
中科院分区：
文献类型：
--
作者：
Hyatt, Janice L.;Moak, Teri;Potter, Philip M.
羧酸酯酶（CE）是一种普遍存在的酶，被认为是负责代谢和解毒的外来生物。许多临床使用的药物包括杜冷丁、利多卡因、卡培他滨和CPT-11都是由这些酶水解的。因此，选择性CE抑制剂的鉴定和应用可能有助于调节体内酯化药物的代谢。最近，我们发现苯并（二苯乙烷-1,2-二酮）是一种有效的选择性ce抑制剂，我们试图评估相关的1,2-二酮对这些酶的抑制活性。生化分析和动力学研究表明，isatins（吲哚-2,3-二酮）在这些分子的不同位置上含有疏水性基团，可以作为有效的特异性CE抑制剂。有趣的是，isatin化合物的抑制效力与其疏水性有关，因此clogP值< 1.25的化合物对酶的抑制作用无效。相反，显示clogP值bbb50的类似物通常在nM范围内产生K-i值。此外，还获得了两种人类ce （hCE1和hiCE）的优秀3D QSAR相关性。虽然isatin类似物在CE抑制方面的效果通常不如苯基化合物，但前者可能是开发用于调节体内药物代谢的抑制剂的有效先导化合物。
Carboxylesterases (CE) are ubiquitous enzymes thought to be responsible for the metabolism and detoxification of xenobiotics. Numerous clinically used drugs including Demerol, lidocaine, capecitabine, and CPT-11 are hydrolyzed by these enzymes. Hence, the identification and application of selective CE inhibitors may prove useful in modulating the metabolism of esterified drugs in vivo. Having recently identified benzil (diphenylethane-1,2-dione) as a potent selective inhibitor of CEs, we sought to evaluate the inhibitory activity of related 1,2-diones toward these enzymes. Biochemical assays and kinetic studies demonstrated that isatins (indole-2,3-diones), containing hydrophobic groups attached at a variety of positions within these molecules, could act as potent, specific CE inhibitors. Interestingly, the inhibitory potency of the isatin compounds was related to their hydrophobicity, such that compounds with clogP values of < 1.25 were ineffective at enzyme inhibition. Conversely, analogs demonstrating clogP values > 5 routinely yielded K-i values in the nM range. Furthermore, excellent 3D QSAR correlates were obtained for two human CEs, hCE1 and hiCE. While the isatin analogues were generally less effective at CE inhibition than the benzils, the former may represent valid lead compounds for the development of inhibitors for use in modulating drug metabolism in vivo.