Ferrocene-functionalized Heteronuclear Organometallic Anticancer Compounds of Ru, Rh, Os, and Ir

Abstract

Since the discovery of cisplatin in the 1960’s, metal-based compounds with anticancer properties have received great attention. While cisplatin is one of the essential front-line anticancer drug, the severe side effects that come with cisplatin treatments are major concerns. Investigations towards the late-transition metals found that ruthenium complexes have high selectivity towards tumour cells. In particular, RuII(η6-arene) complexes with their “piano-stool” geometry have been explicitly developed to anticancer compounds that are highly effective against primary tumours or metastasis. The “piano stool” design allows the complex to be equipped with essential chemical and biological properties that can be modified with ease. Moreover, the interest in introducing multiple metal centres to the complex has increased significantly due to the novel modes of actions that it offers when interacting with possibly more than one target in cancer cells. In this project, ferrocene functionalised N-pyridine-2-carbothioamides (PCAs) were employed as bioactive moieties that coordinate to the metal centre with Fe introduced as an additional metal centre in form of ferrocene. The application of ferrocene in anticancer drug development is well documented and has been shown to often improve the overall cytotoxicity of compounds especially through the generation of reactive oxygen species (ROS) to induce apoptosis. A series of novel ferrocenyl-PCA heterodi- and trinuclear metal-arene complexes was synthesised and characterised in which the metal centre, the arene moiety, the leaving groups and the linker group of the ferrocenyl-PCA moiety were varied systematically to establish structure-activity relationships for this class of complexes. Density functional theory (DFT) calculation was employed to calculate the optimised ground state structures and frequencies for all ligands and complexes synthesised. The electrochemical properties of these compounds were investigated by means of cyclic voltammetry (CV) which showed that the Fc+/Fc redox couples were irreversible. Aqueous stability studies revealed that these complexes undergo hydrolysis readily. Moreover, the results from the biological evaluation of selected heterodinuclear complexes showed that these compounds demonstrated cytotoxicites in the low to moderate micromolar range. These complexes are particularly active in the HCT116 and SW480 cell lines, demonstrating their potential to become a novel class of metallo-anticancer compounds.