Revisiting the head–head dinuclear 1-methyluracil complex of cisplatin: New insights into its solution behavior

Abstract

The head–head dinuclear complex hh-cis-[Pt(NH3)2(1-MeU-N3,O4)2Pt(NH3)2] (NO3)2 (1-MeU=1-methyluracil anion) is known for 30years, yet its solution behavior has not been studied in great detail. It is the precursor of a blue, mixed-valence Pt tetramer with average Pt oxidation state of +2.25, cis-[{Pt(NH3)2(1-MeU-N3,O4)}4]5+, which crystallizes from an acidified aqueous solution of the hh-dimer in the presence of air or an oxidizing agent. As we show in this paper by use of 1H NMR spectroscopy, the hh-dimer undergoes partial dissociation into its starting components cis-Pt(NH3)2(1-MeU-N3)2 and cis-[Pt(NH3)2(H2O)2]2+ when dissolved in water (neutral pH), and rearranges to other complexes. ESI-MS reveals formation of several new species, including of a trinuclear Pt complex, as well as a compound which has undergone partial loss of NH3 ligands. Release of NH3 and formation of NH4+ is independently confirmed in a qualitative test. The visible spectra of aged, deep blue solutions of the hh-dimer unambiguously prove the existence of other species than just the tetranuclear Pt(2.25) compound which contribute to the intense color, with relative amounts being in the low percent-range. These observations, taken together, strongly suggest that “platinum pyrimidine blues” as formed from aquated cisplatin and N1-blocked pyrimidine nucleobases can adopt structures alternative to the “dimer-of-dimer” principle realized in the well known Pt(2.25) structure. The existence of other structures than dimer and “dimer-of-dimer” poses the question whether the widely accepted view that the antitumor activity of these “blues” solely is due to the release of cis-(NH3)2Pt entities, holds up.