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Int. J. Mol. Sci. 2018, 19(7), 2050; https://doi.org/10.3390/ijms19072050

Multi-Acting Mitochondria-Targeted Platinum(IV) Prodrugs of Kiteplatin with α-Lipoic Acid in the Axial Positions

1
Department of Chemistry, University of Bari Aldo Moro, Via E. Orabona 4, 70125 Bari, Italy
2
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy
3
Department of Chemistry, Eastern Michigan University, Ypsilanti, MI 48197, USA
*
Authors to whom correspondence should be addressed.
Received: 20 June 2018 / Revised: 7 July 2018 / Accepted: 12 July 2018 / Published: 14 July 2018
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Abstract

Platinum(II) drugs are activated intracellularly by aquation of the leaving groups and then bind to DNA, forming DNA adducts capable to activate various signal-transduction pathways. Mostly explored in recent years are Pt(IV) complexes which allow the presence of two additional ligands in the axial positions suitable for the attachment of other cancer-targeting ligands. Here we have extended this strategy by coordinating in the axial positions of kiteplatin ([PtCl2(cis-1,4-DACH)], DACH = Diaminocyclohexane) and its CBDCA (1,1-cyclobutanedicarboxylate) analogue the antioxidant α-Lipoic acid (ALA), an inhibitor of the mitochondrial pyruvate dehydrogenase kinase (PDK). The new compounds (cis,trans,cis-[Pt(CBDCA)(ALA)2(cis-1,4-DACH)], 2, and cis,trans,cis-[PtCl2(ALA)2(cis-1,4-DACH)], 3), after intracellular reduction, release the precursor Pt(II) species and two molecules of ALA. The Pt residue is able to target DNA, while ALA could act on mitochondria as activator of the pyruvate dehydrogenase complex, thus suppressing anaerobic glycolysis. Compounds 2 and 3 were tested in vitro on a panel of five human cancer cell lines and compared to cisplatin, oxaliplatin, and kiteplatin. They proved to be much more effective than the reference compounds, with complex 3 most effective in 3D spheroid tumor cultures. Notably, treatment of human A431 carcinoma cells with 2 and 3 did not determine increase of cellular ROS (usually correlated to inhibition of mitochondrial PDK) and did not induce a significant depolarization of the mitochondrial membrane or alteration of other morphological mitochondrial parameters. View Full-Text
Keywords: platinum(IV) complexes; cisplatin; kiteplatin; α-lipoic acid; DNA; mitochondria; tumor spheroids platinum(IV) complexes; cisplatin; kiteplatin; α-lipoic acid; DNA; mitochondria; tumor spheroids
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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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Savino, S.; Marzano, C.; Gandin, V.; Hoeschele, J.D.; Natile, G.; Margiotta, N. Multi-Acting Mitochondria-Targeted Platinum(IV) Prodrugs of Kiteplatin with α-Lipoic Acid in the Axial Positions. Int. J. Mol. Sci. 2018, 19, 2050.

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