Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications.
Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications.
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DOI：
10.1021/acs.chemrev.7b00042
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发表时间：
2017-08-09
期刊：
影响因子：
62.1
通讯作者：
Kalyanaraman B
中科院分区：
文献类型：
--
作者：
Zielonka J;Joseph J;Sikora A;Hardy M;Ouari O;Vasquez-Vivar J;Cheng G;Lopez M;Kalyanaraman B
线粒体被认为是癌症、心血管和神经系统疾病新药设计的最重要靶点之一。目前，将药物特异性递送至线粒体的最有效方式是通过将亲脂性阳离子如烷基三苯基鳞部分共价连接至感兴趣的药效团。其他离域亲脂性阳离子，如罗丹明、天然和合成的靶向肽和纳米颗粒载体，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的电位，可以实现超过1000倍的线粒体浓度。线粒体靶向已被开发用于研究线粒体生理学和功能障碍以及线粒体与其他亚细胞器之间的相互作用，并用于治疗各种疾病，如神经变性和癌症。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测线粒体功能的努力，作为诊断工具和潜在的治疗方法。我们描述了亲脂性阳离子的线粒体积累的物理化学基础，将化合物靶向线粒体的合成化学策略，线粒体探针和传感器，以及生物活性化合物的线粒体靶向的例子。最后，我们回顾了已发表的尝试，应用靶向药物治疗癌症和神经退行性疾病。
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 potentials of cell and mitochondrial membranes, 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.
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DOI：
10.1097/shk.0000000000000478
发表时间：
2016-01
期刊：
Shock (Augusta, Ga.)
影响因子：
--
作者：
Ahmad A;Olah G;Szczesny B;Wood ME;Whiteman M;Szabo C
通讯作者：
Szabo C
影响因子：
5.9
作者：
Anso E;Mullen AR;Felsher DW;Matés JM;Deberardinis RJ;Chandel NS
通讯作者：
Chandel NS
影响因子：
2.8
作者：
Agapova, L. S.;Chernyak, B. V.;Skulachev, V. P.
通讯作者：
Skulachev, V. P.
影响因子：
3.4
作者：
Antonenko, Yuri N.;Nechaeva, Natalya L.;Zorov, Dmitry B.
通讯作者：
Zorov, Dmitry B.
影响因子：
3.5
作者：
Bai, Longxiang;Li, Ziyuan;Schiller, Peter W.
通讯作者：
Schiller, Peter W.