DETERMINATION OF STRUCTURE-ACTIVITY-RELATIONSHIPS OF ANNONACEOUS ACETOGENINS BY INHIBITION OF OXYGEN-UPTAKE IN RAT-LIVER MITOCHONDRIA
DETERMINATION OF STRUCTURE-ACTIVITY-RELATIONSHIPS OF ANNONACEOUS ACETOGENINS BY INHIBITION OF OXYGEN-UPTAKE IN RAT-LIVER MITOCHONDRIA
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DOI：
10.1016/0009-2797(95)03628-y
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发表时间：
1995-10-20
影响因子：
5.1
通讯作者：
MCLAUGHLIN, JL
中科院分区：
文献类型：
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作者：
LANDOLT, JL;AHAMMADSAHIB, KI;MCLAUGHLIN, JL
一组新的天然化合物，番荔枝苷，最近被确定可以在与鱼藤酮相似的作用位点（即线粒体电子传递链的 NADH-泛醌氧化还原酶复合物 I）抑制 ATP 的产生，并具有更高水平的效力。乙酰丙酮苷较早被确定具有杀虫、抗疟、抗菌、抗寄生虫、细胞毒性和作为潜在的新型抗肿瘤剂的体内活性。为了确定这些化合物之间的结构活性关系 (SAR)，在亚细胞水平上，对几种可用的 acetogenins 进行了测试。从大鼠肝线粒体对耗氧量的抑制中获得的数据表明，所有测试的 20 种 acetogenin 均具有活性，IC50 值在 15-800 nM/mg 蛋白质范围内。鱼藤酮的 IC50 值为 17 nM/mg 蛋白质。双相邻THF环乙酰基和双不相邻THF环化合物的活性比单THF环乙酰基高约十倍。总体而言，30-OH 和 31-OH-bullatacinone 的活性最强，并且比鱼藤酮的活性稍高。活性最低的是 4-脱氧双相邻 THF 环化合物，其次是单 THF 环基团。各组之间存在一些差异，例如，在双相邻和单 THF 环组内，α，β-不饱和-γ-内酯的活性低于酮内酯，但对于双不相邻 THF 环乙酰基中的一对，这一观察结果相反。额外的羟基化（最多三个）似乎增加了所有组内的活性。在对 SAR 做出最终决定之前，应对该亚细胞测定（作为体外测定）的结果与体内测定的结果进行额外比较。此外，未来需要对复合物 I 内的确切作用位点和其他可能的作用位点（例如质膜的 NADH 氧化酶）进行研究，以便全面了解这组新的非常有效的化合物的效用和潜力。
A new group of natural compounds, the Annonaceous acetogenins, have recently been determined to inhibit ATP production at a similar site of action and higher levels of potency as rotenone, i.e., at NADH-ubiquinone oxido-reductase, complex I of the mitochondrial electron-transport chain. The acetogenins had earlier been determined to be pesticidal, antimalarial, antimicrobial, anti-parasitic, cytotoxic, and in vivo active as potentially new antitumor agents. In order to determine structural activity relationships (SARs) among these compounds, at the subcellular level, several available acetogenins have been tested. Data obtained, from the inhibition of oxygen consumption by rat liver mitochondria, demonstrated that all of the twenty acetogenins tested are active with IC50 values in the range of 15-800 nM/mg protein. The IC50 value of rotenone was 17 nM/mg protein. The bis-adjacent THF ring acetogenins and the bis-nonadjacent THF ring compounds are about ten times more active than the mono-THF ring acetogenins. Overall, 30-OH and 31-OH-bullatacinone were the most active and were slightly more active than rotenone. The least active were the 4-deoxy bis-adjacent THF ring compounds followed by the mono-THF ring group. There was some variation between the groups, e.g., within the bis-adjacent and mono-THF ring groups, the alpha,beta-unsaturated-gamma-lactones were less active than the keto-lactones, but this observation was reversed for one of the pairs of bis-nonadjacent THF ring acetogenins. Additional hydroxylations, to a maximum of three, seemed to increase activity within all of the groups. Before final decisions on SARs can be made, additional comparisons of the results of this subcellular assay (as an in vitro assay) with the results of in vivo assays should be made. Also, future investigations into the exact site of action within complex I and other possible sites of action (such as the NADH oxidase of plasma membranes) need to be conducted for a mon complete understanding of the utility and potential of this new group of very potent compounds.