Proteins as Carriers for Tumor-inhibiting Metal Complexes

Most of the drugs available on the market for cancer treatment are non-specific and do not explicitly discriminate between healthy and cancerous tissues, which results in limited efficacy and severe side effects. In recent years much research has focused on achieving tumor specificity and selectivity by targeting cytotoxic drugs to cancer cells. One very promising strategy is to coupling anticancer agents to (biological) macromolecular carriers such as antibodies, peptides, carbohydrates, serum proteins, or synthetic polymers for targeting solid tumors. Selective transport of chemotherapeutics into tumorigenic tissue would drastically reduce their adverse effects. Bioorganometallic chemistry is a relatively new but fervent area of research. It offers possibilities for the design and development of metal based drugs for specific therapeutic needs that are not readily accessible to organic compounds. Currently, Ru(II)- and Os(II)-arene complexes have become the focus of interest and some examples appear to be promising anticancer drug candidates. We plan to functionalize these cytotoxic Ru(II)-arene compounds with a maleimide moiety for coupling it to thiol-containing proteins such as human serum albumin (HSA) to achieve a tumor targeting effect. Maleimide is known to react quickly with thiols, which allows selective modification of cysteine-containing proteins, particularly HSA that contains a free thiol at Cys34. Moreover, HSA is a promising drug carrier because of its passive accumulation in solid tumors due to their high metabolic turnover, hypervascularization, defective vascular architecture, and impaired lymphatic drainage. The mechanism by which macromolecules, such as serum proteins, accumulate in tumor tissue has been termed enhanced permeability and retention (EPR) effect. The maleimide-functionalized compounds will be evaluated with regard to anticancer activity, interaction with proteins and DNA and their adducts will be structurally characterized. Structure-activity relationships will be established based on their in vitro anticancer activity and reactivity with biomolecules and provide the basis for defining a lead structure for further biological studies and development.