Ruthenium complex scaffolds for the creation of targeted chemotherapeutics

Cisplatin, a platinum based drug, remains one of the most widely used anti-cancer treatments in the world; it is used alone or in combination therapies in about 50% of all tumor treatments. Its broad applicability is due to a very general mechanism of action: direct damage to DNA. Unfortunately, physically devastating side effects are common, dose limiting, and additional complications include both primary resistance and evolved resistance. Our goal is to enhance the efficacy and tolerability of chemotherapy drugs by utilizing a pro-drug approach using another metal, ruthenium. Ruthenium compounds can damage DNA in a similar manner to cisplatin, but can be but are turned on by light to become toxic only in the areas irradiated. The hope is to use the light to localize the toxic species only to regions of the body that require treatment. We propose a modular strategy to develop a library of compounds that will contain different molecular components to help localize the compounds in cancer cells and adjust their reactivity. The biological activity will be assessed in various cancer cell lines, and the mechanism by which the compounds kill cells will be investigated. These results will help to determine the most appropriate cancer types for the compounds to treat, and if the compounds will be effective in cisplatin resistant cancers. Our long term aim is to develop a targeted chemotherapeutic approach with reduced side effects that can be applied to a variety of types of cancer.