Maleimide-functionalized RuII(η6-arene) complexes as tumour-targeting agents

Abstract

Since the first platinum-based anticancer agent cisplatin was introduced into clinics, inorganic compounds have become popular in the research field of chemotherapeutics. Different metals such as ruthenium, osmium and rhodium were studied and some complexes have already entered clinical studies. As the existing platinum-based anticancer agents show side effects, resistance and lack of selectivity, this research project aimed to develop novel ruthenium-based anticancer agents with improved selectivity for tumour sites. In this work, a series of ruthenium(II) η6-arene complexes containing maleimide functional groups and bidentate bioactive ligand systems were synthesised (Figure 1). A maleimide functional group is capable to couple with thiol groups such as cysteine residues of biomolecules for transport and exploiting selective delivery to the tumour sites due to the permeability and retention (EPR) effect. One of the promising carrier systems is human serum albumin (HSA) which is a protein target for maleimide as it has a free cysteine residue. Moreover, N-substituted 2-pyridinecarbothioamides (PCAs) act as S,N-bidentate ligands and have been reported to be bioactive as gastric mucosal protectants and show low acute toxicity in vivo. These characteristics of PCAs make them ideal candidates as ligands in metallodrug development that can be administered orally. 8-Hydroxylquinoline (8-HQ) derivatives act as N,O-bidentate ligands and have properties, such as a diverse set of bioactivities and therapeutic potential. 8-HQ complexes have properties that make them ideal candidates to overcome current limitations of chemotherapeutics. The synthesised Ru(II) complexes were characterised by melting/decomposition point analysis, NMR spectroscopy and electrospray ionisation (ESI) mass spectrometry. Furthermore, the thiol binding ability of selected complexes was studied by using L-cysteine as a model. The reaction was monitored by 1H NMR and the results showed the complexes are highly selective for thiol groups. Protein (HSA, transferrin and human serum) binding studies with a selected complex were also conducted. The reactions were monitored by size exclusion chromatography hyphenated to inductively coupled plasma mass spectrometry (SEC-UV/vis-ICP-MS) and the results showed the complex is capable of binding to both HSA and transferrin.