Organoruthenium and Osmium Anticancer Complexes Bearing a Maleimide Functional Group: Reactivity to Cysteine, Stability, and Cytotoxicity

Abstract

Targeted delivery provides a means to overcome the systemic toxicity of cancer chemotherapeutics. Maleimide functionalization of anticancer-active metal complexes allows their site-selective covalent conjugation to human serum albumin (HSA) to exploit passive targeting to the tumor site through the enhanced permeability and retention (EPR) effect. By incorporating the maleimide moiety in the monodentate N-donor coligands, a series of [MII(cym)X2] (M=Ru, Os; cym=η6-p-cymene; X=Cl2, Br2, I2, oxalate) complexes was synthesized and characterized. The influence of the metal center, η6-arene, and leaving group X on the chemical and biological properties was studied. The compounds exhibited low stability in dimethyl sulfoxide (DMSO) but were more stable in the 5 % aqueous DMSO solution used in biological assays. Incubation with cysteine as a model for thiol-containing biomolecules demonstrated high reactivity of the maleimide with the thiol group. In in vitro anticancer assays in human colorectal, non-small-cell lung, and cervical carcinoma cells the complexes were good to moderately active with the lowest IC50 value at 8 μM for an osmium–iodido complex.