Abstract:
Since cisplatin has been approved by the FDA in 1978, its anticancer capabilities have opened the field to other metals such as ruthenium-based complexes. Although cisplatin is a highly potent anticancer agent, due to its lack of selectivity it results in a number of side effects. Thus, the search to find new anticancer drug delivery mechanisms is equally as important as finding new anticancer drugs. Ruthenium compounds, in particular RuII(arene) ‘piano stool’ complexes with the general formula of [M(arene)(X)(Y)(Z)], have gained a lot of attraction as they have shown to be effective against primary and metastasised tumours. The arene ring creates a hydrophobic area that allows the complex to pass through the cell membrane into the cell, while the ligands X, Y, and Z can be mono- or multi-dentate and can be fine-tuned to modify the chemical and biological properties of the ruthenium complex. The ruthenium complexes synthesised in this project contain a monodentate N-heterocyclic carbene (NHC) and the biologically active bidentate co-ligands 8-hydroxyquinoline (8-HQ) or 2-pyridinecarbothiomamide (PCA). NHC complexes are typically used in catalysis for their strong metal-carbene bond, and NHC complexes have shown to possess potent antiproliferative activity. Privileged structures, such as 8-HQ, can be used as scaffolds with unique biological and intrinsic drug-like properties and these can be conferred upon metal complexation. PCAs act as S,N-bidentate ligands and are gastric mucosal protectants. Upon their complexation to Ru, they have shown potent antiproliferative activity and are acid stable, making them ideal candidates for oral administration. By synthesising Ru complexes with different biologically active ligands, the respective compounds ideally could have multiple or new modes of action, reducing the development of cancer cell resistance. The synthesised complexes were characterised by nuclear magnetic resonance (NMR) spectroscopy, electrospray ionisation (ESI) mass spectrometry, X-ray diffraction (XRD) analysis when possible, and were found to be stable in DMSO and aqueous solutions. With the lack of selectivity of established anticancer agents in mind, targeting peptides were synthesised and the co-ligand ruthenium complexes were conjugated via an NHC linker to the N-terminus of the peptide whilst on solid support. The Ru(8-HQ)-peptide conjugate was synthesised and purified by RP-HPLC in acceptable yields whereas, only trace amounts of the conjugate were obtained for the PCA ligand. The successful conjugation of derivative Ru(8-HQ) to the peptide opens up the path for the synthesis of other metal-peptide conjugates by solid phase chemistry. This offers a alternative path for metal complexes to be targeted to cancer cells improving their efficacy and reducing potential side effects.