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Int. J. Mol. Sci. 2017, 18(10), 2060;

Mitochondriotropic and Cardioprotective Effects of Triphenylphosphonium-Conjugated Derivatives of the Diterpenoid Isosteviol

Department of Pharmacy, University of Pisa, Bonanno Street, 6, 56120 Pisa, Italy
A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center of Russian Academy of Sciences, Arbuzov Street, 8, 420088 Kazan, Russia
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect, 47, 119991 Moscow, Russia
N. K. Kol’tsov Institute of Developmental Biology, Russian Academy of Sciences, Vavilov Street, 26, 119334 Moscow, Russia
These authors contributed equally to this work.
Author to whom correspondence should be addressed.
Received: 2 August 2017 / Revised: 21 September 2017 / Accepted: 23 September 2017 / Published: 26 September 2017
(This article belongs to the Special Issue Natural and Semi-Synthetic Small Molecules in Drug Discovery)
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Mitochondria play a crucial role in the cell fate; in particular, reducing the accumulation of calcium in the mitochondrial matrix offers cardioprotection. This affect is achieved by a mild depolarization of the mitochondrial membrane potential, which prevents the assembly and opening of the mitochondrial permeability transition pore. For this reason, mitochondria are an attractive target for pharmacological interventions that prevent ischaemia/reperfusion injury. Isosteviol is a diterpenoid created from the acid hydrolysis of Stevia rebaudiana Bertoni (fam. Asteraceae) glycosides that has shown protective effects against ischaemia/reperfusion injury, which are likely mediated through the activation of mitochondrial adenosine tri-phosphate (ATP)-sensitive potassium (mitoKATP) channels. Some triphenylphosphonium (triPP)-conjugated derivatives of isosteviol have been developed, and to evaluate the possible pharmacological benefits that result from these synthetic modifications, in this study, the mitochondriotropic properties of isosteviol and several triPP-conjugates were investigated in rat cardiac mitochondria and in the rat heart cell line H9c2. This study’s main findings highlight the ability of isosteviol to depolarize the mitochondrial membrane potential and reduce calcium uptake by the mitochondria, which are typical functions of mitochondrial potassium channel openings. Moreover, triPP-conjugated derivatives showed a similar behavior to isosteviol but at lower concentrations, indicative of their improved uptake into the mitochondrial matrix. Finally, the cardioprotective property of a selected triPP-conjugated derivative was demonstrated in an in vivo model of acute myocardial infarct. View Full-Text
Keywords: mitochondria; Stevia rebaudiana Bertoni; tetraphenylphosphonium; isosteviol; cardioprotection mitochondria; Stevia rebaudiana Bertoni; tetraphenylphosphonium; isosteviol; cardioprotection

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Testai, L.; Strobykina, I.; Semenov, V.V.; Semenova, M.; Pozzo, E.D.; Martelli, A.; Citi, V.; Martini, C.; Breschi, M.C.; Kataev, V.E.; Calderone, V. Mitochondriotropic and Cardioprotective Effects of Triphenylphosphonium-Conjugated Derivatives of the Diterpenoid Isosteviol. Int. J. Mol. Sci. 2017, 18, 2060.

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