Synthesis, reactions with DNA, and antitumor activity of platinum complexes with aminonitroxyl radicals

Abstract

The work is a review of the data on the synthesis of mono- and biradical PtII complexes with mono- and diaminonitroxyl radicals, as well as of a binuclear complex with diaminonitroxyl radical. A “mild” method is considered for the synthesis of a number of PtIV nitroxyl complexes (9–11), whose lipophilicity varies within a wide range due to the trans-ligands, i.e., the linear aliphatic acid moieties. Correlations between the structures of the complexes, efficiency of their binding to DNA, and the effect of this binding on the DNA stability were established. Cytotoxic properties of the complexes against the HeLa, H1299, and MCF7 tumor cells, the effect of the complexes on the cell cycle, and the p53 protein expression were studied. The data on the antitumor activity of the complexes in the animal tumor model, P388 leukemia, are given. The rate of the development of resistance to complex 10a for P388 leukemia is 2.5 times lower than the corresponding value for cisplatin. It was found that a synergistic enhancement of antitumor activity is observed when low doses of cisplatin and complexes 9b or 10b are simultaneously administered. The specificities of biological activity of the platinum nitroxyl complexes are presumably due to the antioxidant properties of the nitroxyl pharmacophore and the ability of these complexes to cause the p53-independent tumor cell death.