Novel Pt(IV) Prodrugs Displaying Antimitochondrial Effects

Mol Pharm. 2020 Aug 3;17(8):3009-3023. doi: 10.1021/acs.molpharmaceut.0c00417. Epub 2020 Jul 15.


The design, synthesis, characterization, and biological activity of a series of platinum(IV) prodrugs containing the axial ligand 3-(4-phenylquinazoline-2-carboxamido)propanoate (L3) are reported. L3 is a derivative of the quinazolinecarboxamide class of ligands that binds to the translocator protein (TSPO) at the outer mitochondrial membrane. The cytotoxicities of cis,cis,trans-[Pt(NH3)2Cl2(L3)(OH)] (C-Pt1), cis,cis,trans-[Pt(NH3)2Cl2(L3)(BZ)] (C-Pt2), trans-[Pt(DACH)(OX)(L3)(OH)] (C-Pt3), and trans-[Pt(DACH)(OX)(L3)(BZ)] (C-Pt4) (DACH: R,R-diaminocyclohexane, BZ: benzoate, OX: oxalate) in MCF-7 breast cancer and noncancerous MCF-10A epithelial cells were assessed and compared with those of cisplatin, oxaliplatin, and the free ligand L3. Moreover, the cellular uptake, ROS generation, DNA damage, and the effect on the mitochondrial function, mitochondrial membrane potential, and morphology were investigated. Molecular interactions of L3 in the TSPO binding site were studied using molecular docking. The results showed that complex C-Pt1 is the most effective Pt(IV) complex and exerts a multimodal mechanism involving DNA damage, potent ROS production, loss of the mitochondrial membrane potential, and mitochondrial damage.

Keywords: DNA damage; Pt(IV) prodrugs; cisplatin; cytotoxicity; oxaliplatin; translocator protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cisplatin / pharmacology
  • DNA Damage / drug effects
  • Epithelial Cells / drug effects
  • Humans
  • Ligands
  • MCF-7 Cells
  • Mitochondria / drug effects*
  • Mitochondrial Membranes / drug effects
  • Organoplatinum Compounds / pharmacology*
  • Oxaliplatin / pharmacology
  • Prodrugs / pharmacology*
  • Reactive Oxygen Species / metabolism


  • Antineoplastic Agents
  • Ligands
  • Organoplatinum Compounds
  • Prodrugs
  • Reactive Oxygen Species
  • Oxaliplatin
  • Cisplatin