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

Dalton Transactions : an International Journal of Inorganic Chemistry
Salvatore SavinoNicola Margiotta

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.

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Citations

Jan 11, 2020·British Journal of Cancer·Yu LiangXiangjun Meng
Dec 13, 2019·Oxidative Medicine and Cellular Longevity·Tiziana Tataranni, Claudia Piccoli
Jul 18, 2018·International Journal of Molecular Sciences·Salvatore SavinoNicola Margiotta
Mar 13, 2021·Inorganic Chemistry·Moumita MajiArindam Mukherjee
Aug 14, 2021·European Journal of Medicinal Chemistry·Xin QiaoJing-Yuan Xu
Aug 18, 2021·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Andreia ValentePetra Heffeter
Dec 25, 2021·Frontiers in Chemistry·Eoin MoynihanDiego Montagner

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Methods Mentioned

BETA
NMR
fluorescence microscopy

Clinical Trials Mentioned

NCT00069745

Software Mentioned

GraphPad

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