Mechanisms of the Anti-Metastatic and Cytotoxic Properties of Ruthenium Anti-Cancer Drugs

Abstract

Despite significant advances in the treatment of primary tumours through radiotherapy, surgery and chemotherapy; treatment and prevention of metastasis remains problematic. The benefits that traditional Pt chemotherapies have had on patient outcomes have been hampered by drug resistance and severe patient side-effects. These disadvantages have spurred fresh research into other metal-based pharmaceuticals and Ru complexes have been identified as promising drugs for cancer therapy. In this work, the mechanism of action of NAMI-A, KP1019 and other Ru complexes were investigated. A series of RuII complexes containing neutral face-capping sulfur macrocycle ligands, 1,4,7-trithiacyclononane ([9]aneS3), and 1,4,7,10-tetrathiacyclododecane ([12]aneS4) were synthesized, characterized and investigated to determine the significance of the kinetically driven activity of Ru drugs. As these Ru complexes ([RuCl2([9]aneS3)(S-dmso)], [RuBr2([9]aneS3)(S-dmso)], and [RuCl([12]aneS4)(S-dmso)]Cl) have structural similarities, relationships between the kinetic rates of halido ligand substitution (determined by UV-vis spectroscopy) and in vitro activity were established. The ligand 1,4,7-trimethyltriazacyclononane (Me3tacn), is a neutral face capped ligand investigated in this work. The reactivity and biological activity of the RuII/III trimer complex [Ru3Br6(Me3tacn)2]Br was studied. Previous studies have shown that Ru complexes such as NAMI-A and KP1019 behave as pro-drugs, and that their interaction with blood serum proteins is essential to their activity. Structural properties of the adducts of Ru with various serum proteins were revealed with the use X-ray absorption spectroscopy. The nature of Ru interaction with serum proteins was investigated with gel electrophoresis X-ray fluorescence mapping. This work provided insight into the nature of the reactions that occur when Ru pro-drugs are administered intravenously, and the results of these interactions on anti-cancer activity.