Mitochondria are recognized as one of the most important targets for new drug design in cancer, cardiovascular, and neurological diseases. Currently, the most effective way to deliver drugs specifically to mitochondria is by covalent linking a lipophilic cation such as an alkyltriphenylphosphonium moiety to a pharmacophore of interest. Other delocalized lipophilic cations, such as rhodamine, natural and synthetic mitochondria-targeting peptides, and nanoparticle vehicles, have also been used for mitochondrial delivery of small molecules. Depending on the approach used, and the cell and mitochondrial membrane potentials, more than 1000-fold higher mitochondrial concentration can be achieved. Mitochondrial targeting has been developed to study mitochondrial physiology and dysfunction and the interaction between mitochondria and other subcellular organelles and for treatment of a variety of diseases such as neurodegeneration and cancer. In this Review, we discuss efforts to target small-molecule compounds to mitochondria for probing mitochondria function, as diagnostic tools and potential therapeutics. We describe the physicochemical basis for mitochondrial accumulation of lipophilic cations, synthetic chemistry strategies to target compounds to mitochondria, mitochondrial probes, and sensors, and examples of mitochondrial targeting of bioactive compounds. Finally, we review published attempts to apply mitochondria-targeted agents for the treatment of cancer and neurodegenerative diseases.

中文翻译：

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线粒体靶向的三苯基phosph基化合物：合成，作用机理以及治疗和诊断应用

线粒体被认为是癌症，心血管和神经系统疾病中新药设计的最重要目标之一。当前，将药物特异性地递送至线粒体的最有效方法是将亲脂性阳离子（例如烷基三苯基phosph部分）与目标药效团共价连接。其他离域的亲脂性阳离子，如若丹明，天然和合成的线粒体靶向肽，以及纳米颗粒载体，也已用于小分子的线粒体递送。根据所使用的方法以及细胞和线粒体膜电位的不同，可以实现超过1000倍的高线粒体浓度。线粒体靶向已被开发来研究线粒体生理和功能障碍以及线粒体和其他亚细胞器之间的相互作用，并用于治疗多种疾病，例如神经退行性疾病和癌症。在这篇综述中，我们讨论了将小分子化合物靶向线粒体以探索线粒体功能的努力，作为诊断工具和潜在疗法。我们描述了亲脂性阳离子的线粒体积累的理化基础，将化合物靶向线粒体，线粒体探针和传感器的合成化学策略，以及针对生物活性化合物的线粒体靶向的实例。最后，我们回顾了将线粒体靶向药物应用于治疗癌症和神经退行性疾病的尝试。