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

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.

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

“…We have already reported on kiteplatin-Pt(IV) complexes having DCA in the axial positions with the lead compound, cis , trans , cis -[PtCl 2 (DCA) 2 ( cis -1,4-DACH)] showing encouraging antitumor activity also in vivo in the solid syngeneic murine model Lewis Lung Carcinoma [ 24 ]. In this work we have extended the investigation to Pt(IV) kiteplatin derivatives containing, in the axial positions, the antioxidant ALA: namely cis , trans , cis -[Pt(CBDCA)(ALA) 2 ( cis -1,4-DACH)] ( 2 ) and cis , trans , cis -[PtCl 2 (ALA) 2 ( cis -1,4-DACH)] ( 3 ).…”

“…The growth inhibitory effect toward tumor cell lines was evaluated by means of the MTT as previously described [ 24 ]. Cancer cells were seeded in 96-well microplates in growth medium (100 μL, 3–8 × 10 3 cells/well, depending upon the growth characteristics of the cell line) and then incubated in a 5% carbon dioxide atmosphere at 37 °C.…”

“…In order to overcome at least some of these drawbacks, new platinum drugs based on the platinum(IV) core have been developed. In this context, we have recently focused on Pt(IV) complexes [ 22 , 23 ] derived from kiteplatin, [PtCl 2 ( cis -1,4-DACH)] (DACH = diaminocyclohexane; Scheme 2 ) including a derivative having two DCA ligands in axial positions [ 24 ]; the aim was to obtain a dual acting complex endowed with the ability to target both nuclear DNA and mitochondria. Kiteplatin contains an isomeric form of the diamine ligand 1 R ,2 R -DACH present in oxaliplatin and is effective against both cisplatin-resistant (ovarian C13*) and oxaliplatin-resistant (colon LoVo-OXP) cancer cell lines, suggesting that the spectrum of activity of this compound could be different from that of cisplatin and oxaliplatin [ 25 , 26 , 27 , 28 ].…”

MiR-107 confers chemoresistance to colorectal cancer by targeting calcium-binding protein 39

“…In recent years, DCA was found to inhibit the growth of multiple malignancies such as human breast cancer, non-small-cell adenocarcinoma and glioblastoma cell lines; DCA also inhibits endometrial cancer, neuroblastoma and other malignant tumours. [34][35][36] When combined with etoposide and cisplatin, carboplatin, platinum and its metabolite JM118, DCA was found to have significantly increased the antitumour effects. [37][38][39] There are two main mechanisms accounting for DCA's anticancer effect: 1) reversal of the Warburg effect to inhibit cancer cell proliferation and activate caspase-mediated apoptosis and 2) the oxidative elimination of lactic acid by the co-buffer action of pyruvate and hydrogen ions in the mitochondrial matrix.…”

Improving the anticancer activity of platinum(iv) prodrugs using a dual-targeting strategy with a dichloroacetate axial ligand

“…1). [22][23][24] On the other hand, taking the triuoroacetate (TFA) group as the ligand can increase the lipophilicity and possess good ability to be dissociated. 25,26 Therefore, we designed and synthesized Pt(IV) complexes 2a and 2b with TFA as the axial ligand.…”