This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The ultimate aim of this research is to synthesize and characterize new ruthenium and copper complexes with the goal of optimizing their ability to interact with DNA and to establish their ability to disrupt cell proliferation. The key roles that transition metal ions play in biological systems are well established and transition metal complexes are finding increasing usage in clinical medicine including oncology. The platinum-based anticancer drugs cisplatin and carboplatin are the most well known. However, it is important to synthesize new classes of anticancer agents and the design of new potential drugs is increasingly focused on ruthenium complexes. A new class of organometallic ruthenium complexes, [(arene)Ru(XY)Cl]+ (XY = ethylenediamine) have been reported to show significant cytotoxic activity. Copper too has long been used in medical applications and the antitumor properties of some copper complexes have been known since the 1960s. The mechanism of cytotoxicity for ruthenium compounds has not been established. Nucleic acids, particularly DNA, are considered a high probability target. This research is designed to investigate the chemical and biological properties of organometallic and inorganic ruthenium and copper complexes.
We aim to establish that we can prepare complexes of the type [Ru(arene)(XY)Cl]+ that can bind to DNA in a predominantly intercalating fashion. In these complexes XY is a class of ligand that includes biologically strategic thiosemicarbazones (TSCs). Thiosemicarbazones have a versatile range of biological effects such as antiviral, anti-neoplastic and anticancer properties, and we expect to see improved biological activity by coupling with the organometallic ruthenium moiety or attachment to a copper center. We will carry out a number of experiments in order to probe the mode as well as strength of binding to the nucleic acid. We expect to also show that the complexes are cytotoxic to cancer cells and are able to prevent proliferation in vitro. The methods to be used include absorption spectroscopy, thermal denaturation studies, electrochemical and viscometric measurements. Mechanistic studies to determine kinetic and thermodynamic data will be done. Successful completion of these goals will add to the body of knowledge concerning inorganic anticancer agents and will deepen our understanding of the mechanisms occurring at the cellular level. This is crucial for further development of these and other cancer chemotherapies.
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