Biologically Active Metal Complexes: New Designs Inspired by Mechanistic Studies

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We are developing new metal complexes as probes of biological processes and for therapeutic applications. To do this, we design and synthesize molecules and study their reactions in biological environments using spectroscopic methods. These studies will produce compounds that address a primary challenge in cancer research: how to preferentially target cancer cells while leaving normal cells unaffected. This work involves three interrelated themes:******1) In vitro spectroscopy of metal complexes***To explain why some ruthenium and copper complexes have anticancer activity, we will develop spectroscopic techniques to investigate their reactions in cancer cells. One approach will probe interactions of Cu complexes with biomolecules such as proteins and DNA, and processes that lead to the generation of active species. These studies will apply the techniques electron paramagnetic resonance (EPR) and electron nuclear double resonance (ENDOR) to analyze reactions of complexes in whole cells. Another approach will use magnetic resonance imaging (MRI) of Ru complexes containing fluorine to study the effects of low-oxygen environments in tumors. These methods will be used to study the mechanisms of action of new compounds synthesized in our laboratory.******2) Complexes targeting transport into cells***We are developing new metal complexes towards the goal of anticancer agents that have higher activity and lower side effects. To achieve this we are tethering metal complexes to biological compounds that enhance their transport into cells. Many cancer cells have elevated levels of proteins that recognize and internalize specific biomolecules. For example, the iron-transport protein transferrin (TF) is taken up preferentially by many cancer cells. By linking metal complexes to amino acids of TF we will generate new anticancer species and study the protein-mediated transport process. Rapidly growing cancer cells can also have higher levels of vitamin transport proteins. We will harness this property using vitamin molecules linked to metal complexes. A third approach will use short amino acid chains to promote the transport and targeting of metal compounds into cancer cells. ******3) Selectively activated metal complexes***Differences in biological processes in normal and cancer cells mean that metal complexes can undergo distinct reactions in each environment. We are developing Cu and Ru complexes that generate toxic species in the low-oxygen environments found in many tumors, while remaining inactivated in blood or normal tissues. We are also targeting elevated levels of sulfur-containing molecules that are found in many cancer cells. This involves the development of complexes that release nitric oxide, which can be toxic to cells at high concentrations. These compounds will lead to new therapeutics that preferentially kill cancer cells and also can act as probes of biological processes related to tumor growth.