Abstract

Appending lipophilic cations to small molecules has been widely used to produce mitochondria-targeted compounds with specific activities. In this work, we obtained a series of derivatives of the well-known fluorescent dye 7-nitrobenzo-2-oxa-1,3-diazole (NBD). According to the previous data [Denisov et al. (2014) Bioelectrochemistry, 98, 30-38], alkyl derivatives of NBD can uncouple isolated mitochondria at concentration of tens of micromoles despite a high pK_a value (~11) of the dissociating group. Here, a number of triphenylphosphonium (TPP) derivatives linked to NBD via hydrocarbon spacers of varying length (C5, C8, C10, and C12) were synthesized (mitoNBD analogues), which accumulated in the mitochondria in an energy-dependent manner. NBD-C10-TPP (C10-mitoNBD) acted as a protonophore in artificial lipid membranes (liposomes) and uncoupled isolated mitochondria at micromolar concentrations, while the derivative with a shorter linker (NBD-C5-TPP, or C5-mitoNBD) exhibited no such activities. In accordance with this data, C10-mitoNBD was significantly more efficient than C5-mitoNBD in suppressing the growth of Bacillus subtilis. C10-mitoNBD and C12-mitoNBD demonstrated the highest antibacterial activity among the investigated analogues. C10-mitoNBD also exhibited the neuroprotective effect in the rat model of traumatic brain injury.

中文翻译：

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将7-硝基苯并-2-氧杂-1,3-二唑（NBD）连接到三苯基Yi可产生线粒体靶向的质子载体和抗菌剂

摘要

将亲脂性阳离子附加到小分子上已被广泛用于产生具有特定活性的线粒体靶向化合物。在这项工作中，我们获得了一系列著名的荧光染料7-硝基苯并-2-氧杂-1,3-二唑（NBD）的衍生物。根据以前的数据[Denisov等。（2014）生物电化学，98，30-38]，NBD的烷基衍生物可脱开分离以几十微摩尔的浓度线粒体尽管高的pK_一个离解基团的值（〜11）。在此，合成了许多通过不同长度的烃间隔基（C5，C8，C10和C12）与NBD连接的三苯基phosph（TPP）衍生物（mitoNBD类似物），它们以能量依赖的方式积累在线粒体中。NBD-C10-TPP（C10-mitoNBD）在微摩尔浓度下充当人工脂质膜（脂质体）和未偶联的分离线粒体的质子体，而具有较短接头的衍生物（NBD-C5-TPP或C5-mitoNBD）则没有这样的活动。根据该数据，C10-mitoNBD在抑制枯草芽孢杆菌生长方面比C5-mitoNBD明显更有效。。在研究的类似物中，C10-mitoNBD和C12-mitoNBD表现出最高的抗菌活性。C10-mitoNBD在脑外伤大鼠模型中也表现出神经保护作用。