The broad success of Pt(ll) based drugs in human cancer chemotherapy, has led to interest in the potential for another transition metal, Ru (II), as an antineoplastic agent [3]. A number of DMA-binding, cationic dinuclear Ru(ll) polypyridyl complexes have been prepared in racemic form, and preliminary studies in cultured malignant cell lines as well as in isogenic, orthotopic mouse melanoma model show promising antineoplastic activity. It is hypothesized that some of these Ru(ll) complexes can be developed into effective anticancer agents, and that the antitumor activity of Ru(ll) complexes can be predicted on the basis of specific, tunable structural features. We propose to test our hypothesis in studies with these three specific aims: 1. Defining the antineoplastic activity of Ru(ll) complexes in cultured human malignant cells as well as with epithelial cells. These studies will address the hypothesis that some of these Ru(ll) complexes will exhibit antineoplastic activity against an array of histological types of human cancers. 2. Determining the structure-toxicity relationships for Ru(ll) complexes. These studies will address the hypothesis that analogs with 17 A bridges will not be acutely toxic to mice whereas those with the 12 A bridges will be toxic. They will also address the hypothesis that the absolute chirality of the complex can affect the level of toxicity because of the differing ability of the two enantiomers to inhibit acetylcholinesterase activity. 3. Determining the structure-activity relationships for Ru(ll) complexes. These studies will address the hypothesis that the complexes with long, redox-active bridging ligands will be superior to the shorter, non- redox active bridges for intercalation, redox activity, and anti-tumor activity. These studies will also address the hypothesis that optically resolved (enantiopure) complexes will exhibit different DNA binding abilities and therefore exhibit different antineoplastic activity. The use of transition metals, in particular Pt(ll), in human chemotherapy has led to dramatic improvements in the prognosis for a great many cancer patients. Another metal, Ru(ll), has similar properties and is being explored for its potential in chemotherapy. Preliminary results are promising. ? ? ? ?
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