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

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.

• Authors: Salvatore Savino, Cristina Marzano, Valentina Gandin, James D Hoeschele, Giovanni Natile, Nicola Margiotta
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 19 Issue 7 (Jul 14 2018) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 30011897 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Organoplatinum Compounds
• Prodrugs
• Reactive Oxygen Species
• platinum(II)(1,4-diazacycloheptane)dichloride
• Oxaliplatin
• Platinum
• Thioctic Acid
• Cisplatin

Topics

• Antineoplastic Agents (chemistry, metabolism, pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cisplatin (chemistry, metabolism, pharmacology)
• Drug Screening Assays, Antitumor
• Humans
• MCF-7 Cells
• Mitochondria (drug effects, metabolism)
• Mitochondrial Membranes (drug effects, metabolism)
• Molecular Structure
• Organoplatinum Compounds (chemistry, metabolism, pharmacology)
• Oxaliplatin
• Platinum (chemistry, metabolism, pharmacology)
• Prodrugs (chemistry, metabolism, pharmacology)
• Reactive Oxygen Species (metabolism)
• Thioctic Acid (chemistry, metabolism, pharmacology)