Further Studies on Toxic and Radiosensitizing Properties of Ruthenium Complexes of 4-nitroimidazoles

Abstract

Transition metal complexes containing nitroimidazole ligands have been shown previously to act as radiosensitizers of hypoxic cells in vitro. As part of our study on metal-radiosensitizer complexes, we were encouraged by a ruthenium (Ru) sensitizer, RuCl₂(DMSO)₂(4(5)-nitroimidazole)₂, 1, which showed better radiosensitizing properties and lower toxicity than the free ligand. In this study, we have extended our investigation to include the various other substituted 4-nitroimidazoles as ligands. The new Ru complexes, analogues of 1, were synthesized, identified and characterized and their toxicity and radiosensitizing abilities examined in vitro using Chinese hamster ovary (CHO) cells. Like 1, each of these ruthenium complexes has lower CHO hypoxic toxicity than the free ligands alone at equimolar concentration. These newer complexes gave sensitizing enhancement ratio (SER) values of 1·1 to 1·3 at 1·0 × 10⁻⁴ mol dm⁻³ compared with 1·6 for 1. Unlike complex 1, the new complexes do not bind to plasmid DNA (assessed by inhibition of restriction endonuclease activity), possibly because the chloride (Cl⁻) ligand does not dissociate. In addition, the redox potential of the coordinated imidazole ligands is relatively unchanged compared to that of the free ligand. These factors may explain the more favourable properties of 1 compared with those of the new 4-nitroimidazole complexes of Ru.