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      Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

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          Abstract

          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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          Author and article information

          Journal
          2985134R
          2913
          Chem Rev
          Chem. Rev.
          Chemical reviews
          0009-2665
          1520-6890
          26 July 2017
          27 June 2017
          09 August 2017
          09 August 2018
          : 117
          : 15
          : 10043-10120
          Affiliations
          [1 ]Department of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, United States
          [2 ]Free Radical Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, United States
          [3 ]Cancer Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, United States
          [4 ]Institute of Applied Radiation Chemistry, Lodz University of Technology, ul. Wroblewskiego 15, 93-590 Lodz, Poland
          [5 ]Aix Marseille Univ, CNRS, ICR, UMR 7273, 13013 Marseille, France
          [6 ]Translational Biomedical Research Group, Biotechnology Laboratories, Cardiovascular Foundation of Colombia, Carrera 5a No. 6-33, Floridablanca, Santander, Colombia, 681003
          [7 ]Graduate Program of Biomedical Sciences, Faculty of Health, Universidad del Valle, Calle 4B No. 36-00, Cali, Colombia, 760032
          Author notes
          [* ]To whom correspondence should be addressed: B. Kalyanaraman or J. Zielonka, Department of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, United States; balarama@ 123456mcw.edu (B.K.), jzielonk@ 123456mcw.edu (J.Z.); Tel: (414) 955-4000 (B.K.), (414) 955-4789 (J.Z.); Fax: (414) 955-6512
          Article
          PMC5611849 PMC5611849 5611849 nihpa894690
          10.1021/acs.chemrev.7b00042
          5611849
          28654243
          dabc9185-515e-4d87-bcf0-249a28346f53
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