Maleimide-functionalised metal(II)(η6-arene) complexes for tumour targeting

Abstract

Ru(II) η6-arene anticancer complexes have been the core invigoration in the design of organometallic antitumour therapeutics. One of the promising approaches to the design of the next generation chemotherapeutics involves the incorporation of functionalised groups, such that in addition to antitumour efficiency, it would also provide selective tumour targeting. Maleimide-functionalisation of anti-cancer active metal complexes has emerged as a promising strategy, which induces selective covalent conjugation to human serum albumin (HSA), thereby exploiting selective transportation to the tumour site through the enhanced permeability and retention (EPR) effect. In this work, series of Ru(II)η6-arene complexes were synthesised by incorporating the maleimide moiety at different sites of the co-ligand. Furthermore, different structural modifications were carried out to investigate the influence of metal centre, η6-arene fragment and leaving groups. In comparison to the second-row transition metal ruthenium, a third-row metal osmium is considered more inert, and thus the advantages of ruthenium chemistry such as availability of additional coordination sites, alterations in ligand affinity and substitution kinetics, and changes in redox potentials should also be applicable. In this rationale, Os(II) η6-arene complexes were also designed and prepared. The Ru(II) and Os(II) η6-arene complexes bearing the maleimide functionality in both bidentate and monodentate ligand systems were characterised mainly by 1H and 13C{1H} NMR spectroscopy, mass spectrometry, and elemental analysis. A few of these complexes were also subjected to single-crystal X-ray diffraction analysis to obtain the molecular structures. This was followed by stability study in DMSO of complexes with monodentate nitrogen heterocycle-based ligands, to investigate the substitution of the ligand with DMSO. In 100% DMSP, immediate dissociation of the ligands was observed. However, in 5% DMSO/H2O, the complexes were significantly more stable. Representative examples from each series of complexes were characterised with regards to aqueous hydrolysis and conjugation to cysteine. All of the complexes reacted rapidly and successfully with Lcysteine as a model for HSA, however dependence of the metal centre was observed. In biological activity studies, HCT 116 (human colorectal carcinoma) and MDA-MB-231 (human breast adenocarcinoma) cell lines were employed to investigate the preliminary anticancer effect of representative examples.