Alkyl-substituted phenylamino derivatives of 7-nitrobenz-2-oxa-1,3-diazole as uncouplers of oxidative phosphorylation and antibacterial agents: involvement of membrane proteins in the uncoupling action
Alkyl-substituted phenylamino derivatives of 7-nitrobenz-2-oxa-1,3-diazole as uncouplers of oxidative phosphorylation and antibacterial agents: involvement of membrane proteins in the uncoupling action
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DOI：
10.1016/j.bbamem.2016.12.014
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发表时间：
2017-03-01
影响因子：
3.4
通讯作者：
Kotova, Elena A.
中科院分区：
文献类型：
--
作者：
Antonenko, Yuri N.;Denisov, Stepan S.;Kotova, Elena A.
为了寻找新的有效的氧化磷酸化解偶联剂，我们研究了荧光基团7-硝基苯并-2-氧杂-1，3-二氮唑（NBD）的4-芳氨基衍生物。在我们最近的工作中（Denisov等人，Bioelectrochemistry，2014），NBD-缀合的烷基胺（NBD-C-n）显示出解偶联活性。得出的结论是，尽管plc值为约10，预期的阻碍解偶联活性可以通过插入烷基链来克服。文献中有证据表明，在4-氨基NBD基团中引入芳基取代基使plc变为中性值。在这里，我们报告的数据上的性质的一些4-芳氨基衍生物的NBD，即，烷基苯氨基-NBD（C-n-苯基-NBD）与不同的烷基链C-n。通过测量穿过平面双层脂质膜的电流，在中性pH下，C-n-phenyl-NBD的质子发射活性从C-1-到C-6-phenyl-NBD单调增长。所有这些化合物都能增加离体大鼠肝线粒体的呼吸速率，降低膜电位。重要的是，C-6-和C-4-苯基-NBD的解偶联作用被谷氨酸、焦碳酸二乙酯（DEPC）、6-酮胆甾烷醇和羧基糖苷部分逆转，从而指出膜蛋白参与线粒体中C-n-苯基-NBD的解偶联活性。DEPC是谷氨酸-谷氨酸载体（AGC）的抑制剂，其底物的显著再偶联作用首次突出了AGC参与线粒体上有效解偶联剂的作用。C-6-phenyl-NBD对枯草芽孢杆菌有较强的抑菌作用，在亚微摩尔浓度下表现为细胞膜去极化和抑制细菌生长。(C)2016爱思唯尔B. V.保留所有权利。
In search for new effective uncouplers of oxidative phosphorylation, we studied 4-aryl amino derivatives of a fluorescent group 7-nitrobenz-2-oxa-1,3-diazol (NBD). In our recent work (Denisov et al., Bioelectrochemistry, 2014), NBD-conjugated alkyl amines (NBD-C-n) were shown to exhibit uncoupling activity. It was concluded that despite a plc value being about 10, the expected hindering of the uncoupling activity could be overcome by insertion of an alkyl chain. There is evidence in the literature that the introduction of an aryl substituent in the 4-amino NBD group shifts the plc to neutral values. Here we report the data on the properties of a number of 4-arylamino derivatives of NBD, namely, alkylphenyl-amino-NBD (C-n-phenyl-NBD) with varying alkyl chain C-n. By measuring the electrical current across planar bilayer lipid membrane, the protonophoric activity of C-n-phenyl-NBD at neutral pH grew monotonously from C-1- to C-6-phenyl-NBD. All of these compounds increased the respiration rate and reduced the membrane potential of isolated rat liver mitochondria. Importantly, the uncoupling action of C-6- and C-4-phenyl-NBD was partially reversed by glutamate, diethyl pyrocarbonate (DEPC), 6-ketocholestanol, and carboxyatractyloside, thus pointing to the involvement of membrane proteins in the uncoupling activity of C-n-phenyl-NBD in mitochondria. The pronounced recoupling effect of DEPC, an inhibitor of an aspartate-glutamate carrier (AGC), and that of its substrates for the first time highlighted AGC participation in the action of potent uncouplers on mitochondria. C-6-phenyl-NBD produced strong antimicrobial effect on Bacillus subtilis, which manifested itself in cell membrane depolarization and suppression of bacterial growth at submicromolar concentrations. (C) 2016 Elsevier B.V. All rights reserved.