Ruthenium arene complexes as anticancer agents: an XAS study

Abstract

Two Ru(III) complexes that have already entered clinical trials, [ImH]trans-[RuCl4(dmso)(Im)] (NAMI-A, Im = imidazole) and [InH]trans-[RuCl4(Ind)2] (KP1019, Ind = indazole), are potential alternatives to Pt chemotherapeutic drugs since they are effective against cancers untreatable by cisplatin. These compounds have been proposed to operate by an “activation by reduction” process, with a reduction of Ru(III) to the more active Ru(II) species in vivo, which has thus generated an interest towards organometallic Ru(II) arene complexes. The leading complexes of this field would be the RAPTA-C pioneered by Dyson and co-workers which showed anti-metastatic activity akin to NAMI-A and the [Ru(p-cymene)(en)]Cl pioneered by Sadler and co-workers which displayed cytotoxicity in vitro. These compounds show great promise due to the versatility in systematically modifying them in order to exhibit desirable physical, chemical and biological properties, mainly by changing the nature of the arene ligand and introducing different chelating ligands that may enhance selectivity towards tumour cells. Traditional anticancer drugs were designed to target DNA but in recent years, serum proteins have been found to be more relevant for the field of Ru anticancer drugs. In order to improve drug efficacy, an understanding of the mechanisms and speciation of these complexes in biological medium is needed. X-ray absorption spectroscopy (EXAFS, XANES) and X-ray fluorescence mapping (XFM) have been used according to previous methods to study the speciation in biological fluids, extracellular matrix and cells to provide insights into the biological activities of various Ru arene complexes. The compounds were first analysed using UV-Vis for their kinetics but this technique was not sensitive enough to differentiate the speciation products. A library of Ru(II) arene model complexes containing biologically relevant ligands (N/O and S-donors) were synthesized and their structures confirmed using multiple scattering (MS). The Ru compounds reacted under various biological conditions were then analysed using multiple linear regression, and the speciation products formed either by aquation or ligand-exchange were able to be identified. In particular, the results of RAPTA-C in rat blood cells were interesting where large changes in the XAS spectra was observed when red blood cells were present in the samples, which indicates extensive metabolism of Ru in whole blood. XFM was useful in analysing the speciation of the Ru-bound proteins in electrophoresis gels and the preliminary results of NAMI-A, KP1019 and RAPTA-C provided good insights on the different serum protein binding affinity of these complexes, and how it might affect their anticancer properties.