Binding of Organometallic Ruthenium(II) and Osmium(II) Complexes to an Oligonucleotide: A Combined Mass Spectrometric and Theoretical Study

Abstract

A series of ruthenium(II) and osmium(II) p-cymene dichloride complexes with either a pta (1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane) or [pta-Me]Cl ligand which exhibit anticancer activity have been prepared and characterized by 1H and 31P NMR spectroscopy and mass spectrometry. Three of the complexes, viz. [Os(η6-p-cymene)Cl2(pta)] and [M(η6-p-cymene)Cl2(pta-Me)]Cl (M = Ru, Os), have also been characterized by single-crystal X-ray diffraction. The pta complexes are selective anticancer agents, whereas the pta-Me+ complexes are indiscriminate and damage both cancer and healthy cells but represent models for the protonated pta adduct which has been implicated in drug activity. To establish a link between their biological activity and the effect they have on DNA (a likely in vivo target), the reactivity of the complexes toward a 14-mer oligonucleotide (5‘-ATACATGGTACATA-3‘) was studied using electrospray ionization mass spectrometry. It was found that the complexes bind to the oligonucleotide with loss of chloride and in some cases loss of the arene. Loss of arene appears to be most facile with the ruthenium−pta complexes but also takes place with the ruthenium−pta-Me complexes, whereas arene loss is not observed for the osmium complexes. In addition, as pH is reduced, increased binding to the oligonucleotide is observed, as evidenced from mass spectrometric relative intensities. Binding energies between the metal centers and the surrounding ligands were calculated using density functional theory (DFT). The calculated energies rationalize the experimentally observed tendencies for arene loss and show that the pta ligands are relatively strongly bound. Exchange of metal center (ruthenium versus osmium), methylation or protonation of the pta ligand, or change of the arene (p-cymene versus benzene) results in significant differences in the metal−arene binding energies while leaving the metal−phosphine bond strength essentially unchanged. Significantly lower binding energies and reduced hapticity are predicted for the exchange of arene by nucleobases. The latter show higher binding energies for nitrogen σ-bonding than for π-bonding.