METAL-BASED ANTICANCER AGENTS: CHEMISTRY, BIOLOGY AND MEDICINE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The ultimate aim of this research is to synthesize and characterize new ruthenium complexes with the goal of optimizing their ability to interact with DNA and other cellular receptors and establishing their ability to disrupt cell proliferation. The most well-known metal-containing drugs are platinum-based, but, due to their dose-limiting toxicity, it is important to synthesize new classes of anticancer agents. Current research is aimed at the design of new drugs that have enhanced potency, are less toxic, and have a wider spectrum of indication. Such research is increasingly focused on ruthenium complexes and a new class of organometallic ruthenium complexes, [(arene)Ru(LL)Cl]+ (LL = bidentate or monodentate ligands), have been reported to show significant cytotoxic and/or anti-metastatic activity. The mechanism of cytotoxicity for ruthenium compounds has not been equivocally established. The nucleic acids, particularly DNA, are commonly accepted as high- probability targets (similar to the platinum drugs); however proteins and various enzyme systems may also serve as drug targets. The identification of cellular targets is important for further refining strategy when designing drug candidates. This research will investigate the chemical and biological properties of organometallic ruthenium complexes. We have already established that we can prepare complexes of the type [(arene)Ru(LL)Cll]+, where LL is a biologically strategic thiosemicarbazone. These complexes are cytotoxic to cancer cells and can bind to DNA. We will continue to probe the mode as well as strength of binding to DNA. We will also investigate the possibility that our complexes are interacting with biomolecules other than DNA. We will show that the complexes are cytotoxic to cancer cells and are able to suppress proliferation in vitro. In addition, we will examine the cytotoxic effects of the complexes on non-tumorigenic cells. This project is very much in line with the INBRE core principles. The project will enable the undergraduate researchers to participate in a cutting-edge area of medicinal chemistry. This will hopefully foster an interest in graduate studies and the wide diversity of careers in biomedical research.