Probing the interaction of bisintercalating (2,2':6',2″-terpyridine)platinum(II) complexes with glutathione and...

Platinum(II) complexes have demonstrated considerable success in the treatment of cancer, but severe toxic side effects drive the search for new complexes with increased tumour selectivity and better efficacy. A critical concept that has to be considered in the context of designing novel Pt complexes is their interactions with biomolecules other than DNA. To this end, here the interactions of 16 previously reported bisintercalating (2,2':6',2″-terpyridine)platinum(II) complexes, [{Pt(terpy)}₂μ-(X)]ⁿ⁺ (where X is a linker) with glutathione (GSH) by means of ¹H and ¹⁹⁵Pt NMR spectroscopy were investigated. The GSH half-life (GSH t_1/2) was determined following the incubation of each [{Pt(terpy)}₂μ-(X)]ⁿ⁺ complex with GSH (8mM). It was observed that complexes 1-7, 11, 12 and 14-16 reacted more rapidly than cisplatin, whereas complexes 8-10, 13 and 17 reacted more slowly (≥200min). There was no apparent correlation between linker length and the GSH t_1/2. In order to understand these interactions, two complexes: 1 (t_1/2<1min) and a previously studied 17 [Pt(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)] (56MESS) (GSH t_1/2=4080min) were incubated with rabbit plasma. A "metallomics" approach was used to analyse plasma for all platinum species at the 5 and the 60min time point and provided results that were congruent with the reaction of the selected Pt complexes with GSH. Our studies demonstrate that the combined application of NMR spectroscopy, cytotoxicity studies and a metallomics approach can contribute to better understand the interaction of [{Pt(terpy)}₂μ-(X)]ⁿ⁺ complexes with biomolecules to better assess which compounds may be advanced to in vivo studies.