Half-sandwich Anticancer Organometallics Derived from Triazolyl-imidazolium Ligands: From Different Coordination Modes to Heterobimetallic Compounds

Abstract

To overcome the adverse effects and narrow pharmacological spectrum of traditional platinum anticancer agents, a large variety of metallodrugs have been investigated in the search for the next generation cancer therapeutics. Half-sandwich metal complexes are a class of compounds that have portrayed promising anticancer activity. Imidazole is an essential building block of molecules in medicinal chemistry, which is commonly featured in many biologically active compounds. The versatile heterocyclic scaffold enables the design and development of ligand systems suitable for metal coordination. Thionation of the C2 carbon or the alkylation of the endocyclic nitrogen atoms leads to the formation of N-heterocyclic thiones (NHTs) and N-heterocyclic carbene (NHC) ligand precursors, respectively, which were both investigated for their anticancer properties upon coordination to transition metals. An extensive series of asymmetric NHT and NHC compounds derived from an imidazolium scaffold was developed, in which one of the endocyclic nitrogen atoms was alkylated with a methyl or methylpyridyl group, while the other has a pendant triazolyl moiety functionalised with a benzyl or methylferrocene group. The heterocyclic compounds functioned as mono- or multidentate ligand systems generating half-sandwich organometallic complexes of RuII, OsII, RhIII, and IrIII. When the pro-ligands were coordinated to metal centres, the resultant complexes formed pockets that hydrogen bond with the counterion. These pockets were established by the protons of the ligand near the metal centre. Cytotoxicity assays revealed that the ligand precursors showed only moderate to low anticancer activity. Coordination to metal centres resulted in compounds with a varied degree of improvements in cytotoxicity. NHT complexes generally displayed low to moderate cytotoxicity, with the Ir derivative being moderately cytotoxic and accumulating in the cytoplasm of cancer cells. Conversion into the analogous Ir(NHC) derivatives did not result in significant enhancement in cytotoxicity. The low potency of the Ru- and Os(NHC) derivatives was accounted for by their slow to no reactivity with biological molecules. Replacement of the benzyl group with ferrocene significantly improved the cytotoxicity of the compounds and promoted the generation of reactive oxygen species (ROS) in cancer cells. Alternative coordination modes were investigated with the methylpyridine-derived NHC precursors, which resulted in the unexpected formation of bi- and tridentately coordinated Os and Rh complexes. However, the improvement in cytotoxicity was not as pronounced compared to ferrocene-functionalisation. The investigation of various ligand modifications and coordination modes laid the foundation for the determination of structure-(re)activity relationships of these classes of complexes featuring different imidazole-derived ligands.