Design, synthesis and activation of ruthenium arene anticancer complexes

Abstract

The synthesis and characterisation of RuII complexes of the form [(η6-arene)Ru(N,N')X]+ (where N,N' is a bidentate chelating ligand and X is a halogen) are described; including the X-ray crystal structures of four of these complexes. The hydrolysis rates at 310 K of the complexes vary over many orders of magnitude and in some cases are followed by partial arene loss. Density Functional Theory (DFT) calculations suggest that the aquation mechanism occurs via a more associative pathway. The significant cytotoxic activity towards A2780 human ovarian cancer cells of some of the complexes is found to be dependent on the chelating ligand. Selective binding to 9-ethylguanine (9-EtG) but not to 9- ethyladenine (9-EtA) is observed in aqueous solution at 310 K in all cases. The X-ray crystal structure of a RuII arene 9-EtG adduct is also described. DFT calculations show that the 9- EtG nucleobase adducts of all complexes are thermodynamically preferred compared to those of 9-EtA. Preliminary CT-DNA studies in cell-free media suggest that some of these complexes can interact with DNA. A family of piano-stool RuII arene complexes of the form [(η6-arene)Ru(N,N')(L)]2+ (where N,N' is a chelating ligand and L is a pyridine or a pyridine-derivative), that can selectively photodissociate the monodentate ligand (L) when excited with UVA or visible light is described. The X-ray crystal structures of five of these complexes are also discussed. Their photoactivation allows the formation of a reactive aqua species that otherwise would not form in the dark. Results from TD-DFT calculations suggest that all the RuII pyridine complexes follow a relatively similar L-ligand photodissociation mechanism, likely to occur from a series of 3MC triplet states. It is shown how light activation can be used to phototrigger binding of these complexes to nucleobases with specific preference towards 9- EtG over 9-EtA. CT-DNA studies suggest that photoirradiated complexes interact with DNA via a combined coordinative, intercalative, and monofunctional binding mode. Some of the complexes are also cytotoxic against A2780 human ovarian cancer cell line in the absence of irradiation. The possibility of photo(triggering) hydride-transfer reactions using RuII arene complexes, NAD+, and formate as the hydride source under biologically relevant conditions is shown. The reactions occur either upon the spontaneous hydrolysis of a Ru–Cl bond in complexes of the form [(η6-arene)Ru(N,N')Cl]+ (where N,N' is a bidentate chelating ligand) or upon the photolysis of a Ru–N(Py) bond in [(η6-arene)Ru(N,N')Py]2+ (Py is pyridine). A mechanism involving the formation of a stable formate adduct followed by a hydrogen β- elimination is proposed. It is also demonstrated how a hydride-transfer from 1,4-NADH to some RuII arene chlorido complexes can occur in aqueous solution. Neutral RuII arene complexes of the form [(η6-arene)Ru(NH3)Cl2] which are constitutional analogues of cisplatin were synthesised by a novel synthetic method. These analogues display extensive H-bond interactions in the solid state as shown by X-ray crystal structures determination and their biexponential hydrolysis rates at 310 K vary over many orders of magnitude. The complexes are found to readily form mono- and di-guanine adducts upon hydrolysis but are not cytotoxic against the A2780 human ovarian cancer cell line up to the maximum concentration tested (100 μM)