Studies on the photoactivation of two cytotoxic trans,trans,trans-diazidodiaminodihydroxo-Pt(iv) complexes

Abstract

Light-activation of metal ion complexes to cytotoxic species is of interest due to the potential use in anticancer therapy. Two platinum complexes, trans,trans,trans-[Pt(IV)(N(3))(2)(OH)(2)(NH(3))(2)] (3) and trans,trans,trans-[Pt(IV)(N(3))(2)(OH)(2)(py)(NH(3))] (4) were irradiated with either UV (λ = 366 nm) or white fluorescent light and the various photochemical and photobiological phenomena were characterized. HPLC coupled to UV/Vis and MS detection was used to identify photochemical species resulting from irradiation of 4 with UV and white light. These studies showed that various Pt(IV) and Pt(II) products formed during the photolysis. The mass spectra of Pt(IV) complexes showed Pt ions in both the positive as well as the negative mode while Pt(II) complexes resulted in only positively charged Pt(III) ions. Since cellular DNA is considered to be a key target for platinum antitumor drugs, the irreversible platination of calf thymus DNA by the photoactivated Pt(IV) complexes was followed by Atomic Adsorption spectrometry (AAS). The effect of adding chloride or biological reducing agents glutathione (GSH) and ascorbic acid on the rates of DNA platination where also studied. Upon activation by light, both compounds show similar binding behaviour to DNA, but the rates of DNA platination for 3 were faster than for 4. Both chloride and GSH protected DNA from platination by the photoactivated compounds; consistent with the trapping of reactive aqua-Pt species. The presence of ascorbate increased the level of platinum bound to DNA for photoactivated 4 but not for 3. Without photoactivation, little or no DNA platination was observed, either with or without ascorbate or GSH. Cytotoxicity studies with two human cancer cell lines underline the photochemotherapeutic potential of these compounds. Striking is the increase in cytotoxic potency with the replacement of an ammine by a pyridine ligand.