Platinum(IV) Derivatives of [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthro line)] with Diclofenac Ligands in the Axial Positions: A New Class of Potent Multi-action Agents Exhibiting Selectivity to Cancer Cells

The platinum(II) complex [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)](2+) (Pt(II)56MeSS, 1) exhibits high potencyacross numerous cancer cell lines acting by a multimodal mechanism.However, 1 also displays side toxicity and in vivo activity;all details of its mechanism of action are not entirely clear. Here,we describe the synthesis and biological properties of new platinum(IV)prodrugs that combine 1 with one or two axially coordinatedmolecules of diclofenac (DCF), a non-steroidal anti-inflammatory cancer-selectivedrug. The results suggest that these Pt(IV) complexes exhibit mechanismsof action typical for Pt(II) complex 1 and DCF, simultaneously.The presence of DCF ligand(s) in the Pt(IV) complexes promotes theantiproliferative activity and selectivity of 1 by inhibitinglactate transporters, resulting in blockage of the glycolytic processand impairment of mitochondrial potential. Additionally, the investigatedPt(IV) complexes selectively induce cell death in cancer cells, andthe Pt(IV) complexes containing DCF ligands induce hallmarks of immunogeniccell death in cancer cells.