Mitochondrial- and lysosomal-targeted iron chelators for the monitoring and adjustment of cellular labile iron pools

铁对人体的一系列重要功能是必需的。铁的化学性质使它具有很强的反应性，这种反应性既有用，也可能有害。铁在血液中携带氧气的蛋白质血红蛋白中发挥着最明显的积极作用。然而，铁可以通过刺激活性氧（ROS）的形成而造成损害。这反过来又会产生“氧化应激”，改变细胞成分，如蛋白质、脂肪和DNA，导致细胞功能异常，包括可能的死亡。细胞已经进化出保护性的抗氧化机制来对抗这些影响；然而，过量的铁可以克服这些机制。为了诱导这种破坏作用，铁必须以“自由”形式存在于细胞中，即不与其他分子紧密结合。由于蛋白质，特别是铁蛋白的存在，“游离”铁的水平通常保持在很低的水平，铁蛋白可以结合铁，防止它刺激活性氧的形成。然而，最近的研究表明，尽管存在这些铁捕获蛋白，但在健康细胞的不同细胞区室（例如线粒体和溶酶体细胞器）中存在大量的游离铁，这使得它们容易受到氧化损伤和细胞死亡，特别是在存在活性氧或暴露于环境氧化剂（如产生活性氧的阳光）时。由于游离铁的有害作用，铁捕获药物(即。“铁螯合剂”)被认为是一种从这些亚细胞区室中去除多余铁的方法，这些亚细胞区室在氧化应激条件下是有害的。不幸的是，目前铁螯合剂抵消这些影响的有效性大大降低，因为它们要么渗透性低，因此无法进入细胞内靶点，要么渗透性高，因此在给药时非特异性地扩散到所有细胞区室，导致全身铁饥饿和毒性。为了缓解这些问题，人们已经努力开发新的亚细胞细胞器特异性铁螯合剂药物设计策略，但收效甚微。因此，显然有必要开发智能铁螯合剂，这种螯合剂可以专门输送到亚细胞区室，在那里它们可以登记并去除潜在有害的过量铁。我们最近开发了一种很有前途的铁螯合剂HPO-20，专门监测溶酶体细胞器中的游离铁含量。HPO-20对溶酶体的高选择性表明，在正常和氧化应激条件下，对亚细胞区室中游离铁分布的敏感评估向前迈出了相当大的一步。然而，根据目前的文献，没有这样的独家等效化合物来监测线粒体室中的游离铁。在本项目中，我们建议设计一系列新的线粒体特异性铁螯合剂，在给药后直接到达目标亚细胞区室。这些新化合物的独特之处在于，它们提供了记录和去除细胞器中潜在有害残留铁的可能性。因此，它们有可能被用作生物诊断工具或保护剂。例如，我们的化合物有可能防止由有害环境因素引起的铁相关氧化损伤，特别是阳光引起的皮肤损伤。因此，从长远来看，它们有可能被用作防晒霜配方中的光防护成分，并显著减少与阳光有关的皮肤癌。用我们的化合物监测溶酶体和线粒体游离铁含量的可能性也将有助于识别与亚细胞铁错配相关的病理。因此，通过提供综合诊断和预防制度，我们的化合物将对公众健康产生重大的长期影响。

Iron in the body is necessary for a series of vital functions. The chemical nature of iron makes it highly reactive, and this reactivity can be both useful and potentially harmful. Iron plays its most obvious positive role in the oxygen-carrying protein, haemoglobin, in the blood. However, iron can do damage through stimulating the formation of reactive oxygen species (ROS). These in turn generate 'oxidative stress' and modify cellular components such as proteins, fats and DNA, bringing about abnormal cell function, including possible death. Cells have evolved protective anti-oxidant mechanisms to counter these effects; however excess iron can overcome these mechanisms. In order to induce this damaging effect, iron has to be present in cells in a 'free' form, i.e. not tightly bound by other molecules. Levels of 'free' iron are generally kept very low by the presence of proteins, particularly ferritin, that bind the iron and prevent it from stimulating ROS formation. However recent studies have shown that despite these iron trapping proteins, there is a significant amount of free iron in distinct cell compartments (e.g. mitochondrial and lysosomal organelles) of healthy cells that render them susceptible to oxidative damage and cell death especially in presence of ROS or upon exposure to environmental oxidising agents such as sunlight that generate ROS. Because of the harmful role of free iron, iron trapping drugs (i.e. 'iron chelators') have been proposed as a means to remove excess iron from these subcellular compartments that is detrimental in oxidative stress conditions. Unfortunately the effectiveness of current iron chelators to counteract these effects is much reduced because they have either low permeability and therefore are unable to access their intracellular targets or are highly permeable and therefore upon administration non-specifically diffuse in all cell compartments and cause systemic iron starvation and toxicity. Much effort has gone into the development of novel subcellular organelle-specific iron-chelator drug design strategies to alleviate these problems, but with little success. There is therefore a clear need to develop smart iron chelators that could be specifically delivered to subcellular compartments, where they could register and remove potentially harmful excess iron. We have recently developed a promising iron chelator called HPO-20 that exclusively monitors the free iron content in lysosomal organelles. The high selectivity of HPO-20 for lysosomes represents a considerable step forward toward sensitive evaluation of free iron distribution in subcellular compartments under normal and oxidative stress conditions. However based on current literature, there is no such exclusive equivalent compound for monitoring free iron in mitochondrial compartment. In the present project, we propose to design a series of novel protective mitochondria-specific iron chelators that upon administration directly reach the targeted subcellular compartment. These novel compounds are unique in that they provide the possibility to register and remove potentially harmful residual iron in the organelle. So they have the potential to be used either as biological diagnostics tools or as protective agents. For example our compounds have potential to prevent iron-related oxidative injuries caused by harmful environmental agents notably skin damage caused by sunlight. So in the long term they have potential to be used as photoprotective ingredients in sunscreen formulations and to decrease dramatically the sun-related skin cancer. The possibility of monitoring lysosomal and mitochondrial free iron content with our compounds will also help the identification of pathologies related to subcellular iron-misdistribution. Therefore our compounds will have a major long term impact on public health through availability of combined diagnostic and preventive regimes.