A new ruthenium radiosensitizer: RuC12(DMSO) 2(4-Nitroimidazole) 2

Abstract

Earlier studies on Ru complexes, such as, cis-RUCl 2(DMSO) 4, as antineoplastic agents, have suggested a DNA binding mechanism similar to that of the clinically successful platinum complex, cis-diammine(dichloro)platinum(II), (cis-DDP). As part of our study on metal-radiosensitizer complexes, cis-RUCl 2(DMSO) 4 is used as a precursor for synthesis of Ru(Il)-nitroimidazole complexes. These complexes were identified and characterized and their toxicity and radiosensitizing abilities were examined in vitro. In the series of Ru(II)-nitroimidazole complexes synthesized, RuCl 2(DMSO) 2(4-nitroimidazole)2, “Ru-(4-nitro),” was the most effective radiosensitizer. At 200 μM, Ru-(4-nitro) produced a sensitizer enhancement ratio (SER) of 1.6 in hypoxic Chinese hamster ovary (CHO) cells, but did not sensitize oxic CHO cells. Other Ru-nitroimidazole complexes gave SER values of 1.2-1.4 at 200 μM. These Ru-(II)nitroimidazole complexes also showed lower toxicity than the free nitroimidazoles alone at equimolar concentration. The enhanced radiosensitizing effect of Ru-(4-nitro) may be due to the metal's ability to target the sensitizer to DNA, or may be related to changes in reduction potential: from −685 mV for the free ligand to −355 mV and −615 mV for the complex. This complex did not deplete non-protein sulfhydryls (NPSH) at the time intervals and concentrations used. DNA binding was studied using inhibition of restriction enzyme activity on plasmid DNA.