Comparative analysis of cytotoxic effects and intracellular accumulation of platinum(IV) nitroxyl complexes

The relationship between the lipophilicity, cytotoxic effects, and intracellular accumulation for potential antitumor agents, viz., amino complexes of platinum(IV) with the redox-active nitroxyl radicals cis,trans,cis-PtIV(RNH2)(NH3)(OCOR´)2Cl2 (R is 2,2,6,6-tetramethyl-1-oxylpiperidin-4-yl, OCOR´ are n-alkylcarboxylates C2—C8), was studied in comparison with cisplatin. In a series of four platinum nitroxyl complexes (PNCs), an increase in the lipophilicity was found to lead to a considerable increase in the cytotoxicity and the efficiency of accumulation in HeLa cells. However, PNCs are characterized by the slower development of cytotoxic effects after a short time exposure compared with hydrophilic cisplatin. This can be attributed to the fact that PtIV complexes are prodrugs and need to be reduced to chemically more active PtII derivatives in order to exhibit cytotoxic effects.