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Dual-acting antitumor Pt(IV) prodrugs of kiteplatin with dichloroacetate axial ligands

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Abstract

With the aim to obtain dual acting drugs able to target both nuclear DNA and mitochondria, Pt(IV) kiteplatin derivatives having dichloroacetate (DCA) ligands in axial positions have been synthesized. The rather fast hydrolysis (t1/2 of ca. 1 h) and reduction (by ascorbic acid) of these Pt(IV) derivatives did not impede a potent pharmacological effect on tumor cells. Moreover, similarly to kiteplatin, also the Pt(IV)-DCA compounds proved to be capable of overcoming oxaliplatin-resistance, which is particularly important in view of the fact that metastatic colorectal cancer is the third most common cancer in males and the second in females. The possible role of DCA released by the Pt(IV) compounds in eliciting the antiproliferative activity has also been investigated. Pt(IV)-DCA compounds determine a substantial increase of ROS production, blockage of oxidative phosphorylation, hypopolarization of the mitochondrial membrane, and caspase-3/7 mediated apoptotic cell death.

Graphical abstract: Dual-acting antitumor Pt(iv) prodrugs of kiteplatin with dichloroacetate axial ligands

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Publication details

The article was received on 20 Feb 2018, accepted on 06 May 2018 and first published on 08 May 2018


Article type: Paper
DOI: 10.1039/C8DT00686E
Citation: Dalton Trans., 2018, Advance Article
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    Dual-acting antitumor Pt(IV) prodrugs of kiteplatin with dichloroacetate axial ligands

    S. Savino, V. Gandin, J. D. Hoeschele, C. Marzano, G. Natile and N. Margiotta, Dalton Trans., 2018, Advance Article , DOI: 10.1039/C8DT00686E

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