Ruthenium nitroimidazole complexes as radiosensitizers
Creators: name: Chan, Peter Ka-Lin
Publisher: name: University of British Columbia
Year: 2010

description: Local control of tumours by radiotherapy may fail due to the presence of regions of hypoxic cells. Radiosensitizers, such as nitroimidazoles, enhance killing of the resistant cells by ionizing radiation. However, dose limiting side-effects have prevented the attainment of maximum sensitization. The successful chemotherapeutic drug, cis-diamminedichloroplatinum(II) (cis-DDP), and analogues show moderate radiosensitizing effects, possibly because of binding to DNA. A rationale is then to use the DNA binding property of a metal to carry a sensitizer to the target of radiation damage, DNA, thereby improving the radiosensitizing effect while reducing the toxic side-effects of nitroimidazoles. The complex cis-RuCI₂(dmso)₄ was used as a precursor for synthesis of Ru(II)-nitroimidazole complexes because of its anti-tumour and DNA binding activities. A series of Ru(II) complexes of formulation RuCI₂(dmso)₂Ln, where dmso is S-bonded dimethyl sulphoxide, L = a nitroimidazole, and n=1 or 2, has been synthesized and characterized, and their toxicities and radiosensitizing abilities examined in vitro. When L = 2-nitroimidazole or a substituted-2-nitroimidazole, n = 2, but the nitroimidazole ligands dissociate in aqueous medium. With L = the 5-nitroimidazole, metronidazole, n=2, the sensitizing ability of the six-coordinate cis complex was disappointing with sensitizer enhancement ratio (SER) of 1.2 in hypoxic Chinese hamster ovary (CHO) cells. A series of 4-nitroimidazoles ligands was then studied. With L = 4-nitroimidazole (4-NO₂-Im), 1-(1' -aziridinyl-2' -propanol)-2-methyl-4-nitroimidazole (RSU-1170), 2-(1,2-dimethyl-4-nitroimidazolyl)-2-aminoethanol (RSU-3083), and 1-methyl-4-nitro-5-phenoxyimidazole (RSU-3100), n=2 and the six coordinate complexes appear to be of all cis geometry. The NMe-4-NO₂-Im ligand (n=1) chelates through the imidazole-N and the oxygen of NO₂ group as evidenced from spectroscopic data. Coordination via the nitrito group is uncommon and other examples involving nitroimidazole ligands have not been reported. For the 1-methyl-5-(2'-thioimidazolyl)-4-nitroimidazole (RSU-3159) ligand (n=1), binding to Ru occurs through the thioether and chelation may occur through the imidazole-NCH₃. In this series of Ru(II)-4-nitroimidazole complexes studied, RuC1₂(dmso)₂-NO₂-Im)₂, 5, was the most effective radiosensitizer (SER = 1.6 at 200 ,μM) and is better than the clinically used misonidazole (SER = 1.3 at 200 μM). In addition, 5 did not sensitize oxic CHO cells. Other Ru-N-substituted-4-nitroimidazole complexes gave SER values of 1.1-1.4 at 100-200 μM. Complex 5 also produced a dose-dependent increase in genotoxic activity (as measured by the in vitro induction of chromosome aberrations in CHO cells), which is similar to that of misonidazole but much less than that of c/s-DDP. Two changes in ancillary ligands and geometry of complexes were also examined: replacement of (i) dmso by tmso (tetramethylene sulphoxide), (ii) C1⁻ by Br⁻. The Ru-nitroimidazole complexes were synthesized from the precursors RuCl₂(tmso)₄ and trans-RuBr₂(dmso)₄. In this series of complexes, only RuCl₂(tmso)₂(4-NO₂-Im)₂, 15, and RuCl₂(tmso)₂(SR-2508), 18, have significantly higher SER values (1.6 and 1.5, respectively) than their corresponding nitroimidazole ligands. The tmso complexes of 2-NO₂-Im derivatives were more stable than the dmso series in aqueous solution with respect to the dissociation of the nitroimidazole ligands, which might be due to the improved lipophilicity of tmso complexes. Complex 18. is suggested to be penta-coordinated from XPS and ir data. The RuBr₂(dmso)₂(4-NO₂-Im)₂ was a less effective sensitizer (SER = 1.3 at 200 μM) than the dichloro analogue which may result from different geometrical structures or different behaviour in aqueous solution chemistry. The enhanced radiosensitizing effect over the corresponding free nitroimidazole ligand observed for complexes 5, 15 and 18 may depend on: (a) the metal's ability to target the sensitizer to DNA; complex 5 does bind to DNA, dissociation of C1⁻ perhaps facilitating the reaction; (b) the increase in reduction potential or (c) an increase in lipophilicity of the nitroimidazole ligand on coordination. However, the enhanced radiosensitization does not result from depletion of non-protein thiols. In the present study, the Ru complexes are less toxic than their corresponding nitroimiazole ligands in vitro. The radiosensitization and toxicity of the complexes 5, 15 and 18 are better than those of the free nitroimidazole ligands and the clinically used radiosensitizer, misonidazole. The data encourage further investigations of the use of transition metal complexes as radiosensitizers to combat the hypoxic tumour cells. [Formula Omitted]