Essential structural factors of annonaceous acetogenins as potent inhibitors of mitochondrial complex I
Essential structural factors of annonaceous acetogenins as potent inhibitors of mitochondrial complex I
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DOI：
10.1016/s0005-2728(98)00097-8
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发表时间：
1998-07-20
影响因子：
4.3
通讯作者：
McLaughlin, JL
中科院分区：
文献类型：
--
作者：
Miyoshi, H;Ohshima, M;McLaughlin, JL
番荔枝内酯是已知的牛心线粒体复合体I抑制剂中最有效的，这些抑制剂在酶的末端电子转移步骤，以类似于通常的复合体I抑制剂的方式发挥作用，如胡椒素A和鱼藤酮；然而，乙酰生素和这些已知的复合体I抑制剂之间的结构相似性并不明显。系统地制备了一套分离的天然乙酰生素，并研究了它们与牛心线粒体复合体I的抑制作用，以确定这些抑制剂的基本结构因素，以展示强大的活性。尽管具有很强的活性，但乙酰生素的结构要求并不是特别严格，仍然有些模棱两可。最常见的结构单元，如相邻的双四氢呋喃(THF)环和4位和/或10位的羟基，并不是显示出有效活性所必需的。令人惊讶的是，围绕四氢呋喃环的立体化学似乎并不重要，这一点得到了详尽的构象空间搜索分析的证实，表明模型化合物在四氢呋喃部分周围有不同的立体化学排列，具有相当好的叠加性。连接四氢呋喃和α，β-不饱和伽马-内酯环部分的烷基间隔基团的适当长度和灵活性对于有效的活性是必不可少的。这可能是由于间隔物部分的某种特定构象所致，它调节两个环部分定位到酶上的最佳空间位置。因此，我们认为，最佳抑制所需的乙酰生素的结构特异性与常见的复合体I抑制剂显著不同，后者的基本结构单元排列紧凑，定义方便。通过与其他生物活性的比较，讨论了化合物I抑制的构效关系。(C)1998 Elsevier Science B.V.保留所有权利。
The annonaceous acetogenins are the most potent of the known inhibitors of bovine heart mitochondrial complex I. These inhibitors act, at the terminal electron transfer step of the enzyme, in a similar way to the usual complex I inhibitors, such as piericidin A and rotenone; however, structural similarities are not apparent between the acetogenins and these known complex I inhibitors. A systematic set of isolated natural acetogenins was prepared and examined for their inhibitory actions with bovine heart mitochondrial complex I to identify the essential structural factors of these inhibitors for the exhibition of potent activity. Despite their very potent activity, the structural requirements of the acetogenins are not particularly rigid and remain somewhat ambiguous. The most common structural units, such as adjacent bis-tetrahydrofuran (THF) rings and hydroxyl groups in the 4- and/or 10-positions, were not essential for exhibiting potent activity. The stereochemistry surrounding the THF rings, surprisingly, seemed to be unimportant, which was corroborated by an exhaustive conformational space search analysis, indicating that the model compounds, with different stereochemical arrangements around the THF moieties, were in fairly good superimposition. Proper length and flexibility of the alkyl spacer moiety, which links the THF and the alpha,beta-unsaturated gamma-lactone ring moieties, were essential for the potent activity. This probably results from some sort of specific conformation of the spacer moiety which regulates the two ring moieties to locate into an optimal spatial position on the enzyme. It is, therefore, suggested that the structural specificity of the acetogenins, required for optimum inhibition, differs significantly from that of the common complex I inhibitors in which essential structural units are compactly arranged and conveniently defined. The structure-activity profile for complex I inhibition is discussed in comparison with those for other biological activities. (C) 1998 Elsevier Science B.V. All rights reserved.