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 1 H and 31 P NMR spectroscopy and mass spectrometry. Three of the complexes, viz. [Os(η 6 -p-cymene)Cl 2 (pta)] and [M(η 6 -pcymene)Cl 2 (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.

Mass spectrometry as a powerful tool to study therapeutic metallodrugs speciation mechanisms: Current frontiers and perspectives

“…[84][85][86] In the cases of angiotensin and bombesin, the fragmentation was performed using CID, while additional data were obtained using ECD. The results showed that the primary binding sites of such complexes were methionine and histidine residues, with phenylalanine being a potential secondary site The potential interaction of Ru(II), [87][88][89][90] Ru(III) [90,91] and dinuclear Ru(II) [92] anticancer agents towards oligonucleotides was also studied by ESI-MS. For instance, RAPTA derivatives as well as their osmium analogues were investigated for their reactivity towards a 14-mer single stranded oligonucleotide. [89] The results showed that while RAPTA-C gives rise to Ru-oligonucleotide mono-adducts following detachment of the arene, the osmium analogue forms both mono-and bis-adducts with maintenance of the arene moiety.…”

Aqueous phase carbon dioxide and bicarbonate hydrogenation catalyzed by cyclopentadienyl ruthenium complexes

“…We have been interested for some years in the applications of arene and cyclopentadienyl Ru complexes bearing the water-soluble monodentate phosphine PTA in selective hydrogenation reactions, 9,13 and in medicinal applications, 11,12,14 -17 and recently extended these studies to other transition metals 18,19 and ligand modifications to observe their implications in catalysis; 20 -23 the various aspects of PTA chemistry have been recently reviewed. 24 Under hydrogenation conditions, (pentamethyl) cyclopentadienyl Ru PTA complexes usually showed higher stability than the corresponding arene complexes, thus they are reasonable candidates as catalysts for CO 2 hydrogenation.…”

Platinated DNA oligonucleotides: new probes forming ultrastable conjugates with graphene oxide

“…Out of the complexes formed between cisplatin/A15, HAuCl4/A15, Hg 2+ /T15 and Ag + /C15, only the cisplatin adduct is stable under the denaturing gel electrophoresis condition. Each Pt-nucleobase bond gives a positive charge and thus makes DNA a zwitterionic 15 polymer. This allows ultrafast adsorption of DNA by graphene oxide (GO) and the adsorbed complex is highly stable.…”

“…In the first two cases, an A15 DNA (e.g. a 15-mer DNA with all adenine bases) is respectively reacted with 15 cisplatin and HAuCl4. Pt 2+ and Au 3+ have the same electronic structure and are right next to each other the periodic table, forming a good pair for comparison.…”

“…When a thiol containing peptide, GSH, was added, no DNA displacement was observed for either sample ( Figure 4E). We used GSH since it 15 might bind to platinum and thus weaken the DNA adsorption affinity. This set of experiments established the thermodynamic stability of the platinated DNA/GO interaction.…”