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

摘要

The platinum­(II) complex [Pt­(1S,2S-diaminocyclohexane)­(5,6-dimethyl-1,10-phenanthroline)]2+ (PtII56MeSS, 1) exhibits high potency across 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 coordinated molecules of diclofenac (DCF), a non-steroidal anti-inflammatory cancer-selective drug. The results suggest that these Pt­(IV) complexes exhibit mechanisms of action typical for Pt­(II) complex 1 and DCF, simultaneously. The presence of DCF ligand(s) in the Pt­(IV) complexes promotes the antiproliferative activity and selectivity of 1 by inhibiting lactate transporters, resulting in blockage of the glycolytic process and impairment of mitochondrial potential. Additionally, the investigated Pt­(IV) complexes selectively induce cell death in cancer cells, and the Pt­(IV) complexes containing DCF ligands induce hallmarks of immunogenic cell death in cancer cells.