Radiosensitization by Metal Complexes of 4(5)-nitroimidazole

Summary

Four closely-related cis-platinum (Pt) complexes of 4(5)-nitroimidazole have been examined with respect to properties of radiobiological interest, to test the hypothesis that targeting a nitroimidazole (NO₂Im) to DNA could enhance its radiosensitizing ability: I [PtCl₂(5-NO₂Im)₂]; II [PtCl₂(4-NO₂Im)₂]; III [PtCl₂(NH₃)(5-NO₂Im)]; IV [PtCl₂(NH₃)(4-NO₂Im)]. The reduction potential was affected to the same extent on metal binding in all of the complexes (ΔE_1/2 = + 200 mV, cf. ligand measured polographically). Higher sensitization by 5-NO₂ complexes I, III (cf. II, IV) was found. Only the mono complexes III and IV bind to DNA (in an assay using inhibition of restriction endonuclease activity); these radiosensitize as well as, or better than, free ligand in hypoxic CHO cells, and better than the bis complexes (I and II). The toxicity of the mono complexes is higher than ligand, and parallels the binding (III, IV, mono bis analogues). The complexes are compared with 4-nitroimidazole complexes of ruthenium, with respect to toxicity, binding and radiosensitization.