Binding Mode of 2-amino-5-nitrothiazole (ANT) in Platinum Complexes, Trans-[PtCl₂(ANT)₂], Affects DNA Binding, Toxicity and Radiosensitizing Ability

Summary

The radiosensitizer 2-amino-5-nitrothiazole (ANT) can react with platinum to form many products because of the availability of two potential nitrogen donors as ligands for metals. Two of these complexes, both with two ANT molecules in the trans configuration, differ because of their linkages. In the first, Pt is bound to ANT via the amine group (A) and in the second via the thiazole ring nitrogen (R). Isomer R is a better radiosensitizer than A in hypoxic Chinese hamster ovary cells, giving enhancement ratios of 1·6 versus 1·15 with 100 µmol dm⁻³ complex. The ring-bound isomer also exhibits higher toxicity than the amine bound in air and under conditions of hypoxia. Sensitization by isomer R is much higher under conditions of hypoxia than in air. In an assay to assess DNA binding, isomer R inhibited restriction enzyme cleavage of DNA but isomer A did not (up to 6 h at 300 µmol dm⁻³). It appears from this study on two very similar complexes that the complex which exhibits stronger binding may be targetting the radiosensitizer to the DNA, resulting in greatly improved sensitization.