Influence of Oxygenation on the Reactivity of Ruthenium−Thiolato Bonds in Arene Anticancer Complexes: Insights from XAS and DFT

Abstract

Thiolate ligand oxygenation is believed to activate cytotoxic half-sandwich [(eta(6)-arene)Ru(en)(SR)](+) complexes toward DNA binding. We have made detailed comparisons of the nature of the Ru-S bond in the parent thiolato complexes and mono- (sulfenato) and bis- (sulfinato) oxygenated species including the influence of substituents on the sulfur and arene. Sulfur K-edge XAS indicates that S(3p) donation into the Ru(4d) manifold depends strongly on the oxidation state of the sulfur atom, whereas Ru K-edge data suggest little change at the metal center. DFT results are in agreement with the experimental data and allow a more detailed analysis of the electronic contributions to the Ru-S bond. Overall, the total ligand charge donation to the metal center remains essentially unchanged upon ligand oxygenation, but the origin of the donation differs markedly. In sulfenato complexes, the terminal oxo group makes a large contribution to charge donation and even small electronic changes in the thiolato complexes are amplified upon ligand oxygenation, an observation which carries direct implications for the biological activity of this family of complexes. Details of Ru-S bonding in the mono-oxygenated complexes suggest that these should be most susceptible to ligand exchange, yet only if protonation of the terminal oxo group can occur. The potential consequences of these results for biological activation are discussed.

Palladium and half sandwich ruthenium(II) complexes of selenated and tellurated benzotriazoles: Synthesis, structural aspects and catalytic applications

“…Chiral cationic (g 6 -arene)(pyridylamino)ruthenium(II)-complexes act as enantioselective catalysts for the Diels-Alder reactions with good exo:endo selectivity [20]. The half sandwich compounds of Ru(II) show promising anticancer activity [21][22][23][24][25] cytotoxic half sandwich [Ru(g 6 -arene)(en)(SR)] + complexes toward DNA binding [26]. Ru (II)-arene complexes with pyrone-derived ligands are rendered active against cancer cells by replacement of the coordinated (O,O) donor with (S,O) donor [27].…”

Electrophilic Activation of Oxidized Sulfur Ligands and Implications for the Biological Activity of Ruthenium(II) Arene Anticancer Complexes

“…This is consistent with our previous observation that the RuSOR bond in sulfenato complexes involves the SO π bond, whereas this is not true for sulfinato complexes. 9 Furthermore, we note that decreased charge donation in these complexes is not compensated by the ancillary ligands, leading to increased electron deficiency at the metal center. Formal NBO-derived RuS bond orders were obtained for 1a (0.74) and 1a aq (0.72) but were not observed upon greater perturbation in 1aZn 2+ and 1aH + .…”

“…These results are consistent with the anticipated effects of Lewis acid perturbations on the nature of the Ru-SO 2 R bonding. 9 Computational results were also obtained on the protonated model 2aH + , which could not be investigated experimentally. Overall results from protonation of a single terminal oxo in the sulfinato ligand generates qualitatively similar results to that observed upon Zn 2+ binding (2aZn 2+ ).…”

“…The indirect effect of this interaction upon the RuS σ* orbital is extremely small, reflecting the fact that contributions from the terminal oxo groups into this orbital are relatively small in the sulfinato complexes. 9 Effect of Perturbations on Sulfenato Complex. The reasonable agreement between experimental and computational data obtained for the sulfinato complexes under differing environments, as well as previous success of our DFT results in the solid state, 9 provides us with sufficient confidence that an in silico exploration of the effect of solvation (1a aq ), protonation (1aH + ), and Zn 2+ perturbation (1aZn 2+ ) is appropriate.…”

“…9 We thus seek to explore the effect of exogenous metal ions on the bonding in Ru II arene complexes to provide insights into the effect of protonation on these species. Particular attention is paid to sulfenato species due to their importance in the proposed mode of action, although the effect on sulfinato species is also explored for comparative purposes.…”