Reversible Activation Dynamics of Tethered Ruthenium (II) Arene Complexes

Resumo

Cancer is one of the major causes of death worldwide. There are many types of chemotherapeutic drugs and cisplatin, the first metal-based anticancer agent, is one of the most widely used. Its success to treat several tumours has triggered the investigation of other metal-based agents with cytotoxic activity in cancer research. Ruthenium organometallic complexes have been in the last decade one of the most promising findings due to their inherent anticancer activity and to the possibility of presenting a different cytotoxic profile than that of platinum-based drugs. In fact, some RuIII complexes are currently undergoing clinical trials. A new family of ruthenium(II) arene compounds of general formula [Ru(η6:κ1-arene:Z)(XY)]n+, where arene:Z is a hemilabile tethering ligand and XY is a chelating bidentate ligand has recently been reported. The donor group Z offers two reversible functionalities: (i) binding to the RuII centre to form a closed tether-ring complex (inactive form), or (ii) dissociation from the RuII centre (as a pendant arm) to afford an open-tether complex (active species). This type of complexes can be useful tools to target selectively the acidic microenvironment of the tumour, exploiting the metabolism of the cancer cell. It is known that cancer metabolism is characterized by the preference, even in the presence of oxygen, for 'aerobic' glycolysis, a phenomenon known as the Warburg effect. As a result, accumulation of lactate influences the acidity of the extracellular pH (values as low as 6.2 vs 7.3 in normal cells). This difference can be advantageous in the design of (pro-)drugs that activate selectively at low pH. In this context we propose to explore tethered ruthenium(II) arene complexes, of general formula [Ru(η6:κ1-arene:Z)(XY)]n+, as promising scaffolds to afford reversible pH-dependent activatable metallodrugs. This dissertation focuses in the structural modifications of the building blocks that constitute the ruthenium(II) tether complexes by varying (i) the hemilabile ligand (arene:Z), and (ii) the chelating ligand (XY), in order to finely tune the Ru–Z bond activation. Following an introduction to the field of metals in medicine in Chapter 1, Chapter 2 compiles the structure-activation relationship study of ruthenium(II) tether complexes that helped us understand how the tether arm influences the ring-opening process. This provides valuable information about how both length and rigidity of the tethering arm, and nature of the donor atom, are important features that play a crucial role in the activation of the Ru–Z bond to afford the open-tether (activated) species. Compounds bearing 2-aminobiphenyl and phenylacetic acid as hemilabile ligand were chosen as promising activatable platforms for further investigation. In Chapter 3, we investigated in depth the scaffold [Ru{η6:κ1-C6H5(C6H4)NH2}(XY)]n+ (2-aminobiphenyl as hemilabile arene:Z ligand) bearing different chelating XY ligands. Understanding the dynamics that control the opening of these tether complexes is crucial for rationally designing pro-drugs with controlled activation profiles prior attack of the bond to biological target attack. For this reason, the activation of the rutheniumnitrogen bond was explored in non-aqueous (dimethylsulfoxide and methanol) and aqueous solvents. Importantly, these complexes were able to afford open species at different pH values in water. Since the open species, [Ru{η6-C6H5(C6H4)NH3}(XY)Cl]n+, can undergo protonation of the pendant NH2 rendering the nitrogen unable to coordinate to the RuII, we studied the reversible protonation and deprotonation phenomena for this type of compounds to better understand the compounds’ aqueous dynamics. Also, we investigated the interaction of our switchable system with a model nucleobase. In Chapter 4, we explored complexes with formula [Ru(η6-C6H5CH2COOH)(XY)Cl]n+, bearing phenylacetic acid as hemilabile ligand. A detailed study about the speciation in aqueous solution of a series of complexes bearing different XY ligands is described. We also investigated the ring-opening reaction for their analogue closed-tether complexes to prove that κ1O-dissociation from the ruthenium(II) centre can be tailored under acidic conditions by a reversible pH-mediated activation process. Finally, we explored the capability of these complexes to undergo intracellular hydrogen-transfer reactions. In Chapter 5, we studied how the tether chelate affects stability and activation of this type of ruthenium(II) arene complexes. In order to do this, we compared the reactivity of the RuZ bond in closed-tether versus their un-tether counterparts. In addition, we investigated the possibility of triggering the RuZ bond activation of closed-tether complexes at neutral pH upon photo-irradiation. DFT calculations were carried out to support the experimental results. Finally, in Chapter 6, we studied the possibility to activate the Ru–Z bond in the closed-tether complexes via a solid-state reaction in the presence of vaporous reactants to investigate their potential development as gas sensors. The reversibility of the system was further investigated by different solid state techniques, showing the great versatility that these complexes can offer in the organometallic field.