In the broadest sense, the long term objective of this research project is to develop novel structural analogs of the anticancer compound cis- Pt(NH3)2Cl2, cisplatin, as well as to contribute to the understanding of the mechanism of action of platinum antitumor drugs. Within its context, the specific aims of this research are: (1) To determine whether the selective substitution of the ammine (-NH3) ligands of the cisplatin complex by a series of other ligands, including imidazole, thiazole and oxazole derivatives will result in increased antitumor activity or decreased toxicity; (2) To obtain structural information on the interaction of the new platinum complexes with DNA; and (3) To obtain information about the mechanism of action of """"""""second generation"""""""" platinum antitumor complexes of the type cis-[Pt(NH3)2(A)Cl]+, where A stands for a planar nitrogen-donor ligand. In order to accomplish these goals, a series of new platinum complexes will be prepared. The synthetic approach will be focused in complexes with formulas cis-[Pt(NH3)2(A)Cl]+ and cis-[Pt(NH3)(A)Cl2, where A stands for an azole derivative. The cationic complexes are expected to possess a different mechanism for interaction with DNA as is seemingly the case for the analogous pyridine complexes that have been reported in the literature. The interaction of the new complexes with plasmid DNA, calf thymus DNA, and polynucleotides will be examined using biophysical and biochemical techniques. Raman spectroscopy will be used to asses their binding sites, and to characterize the perturbations to DNA secondary ad tertiary structure induced by these new complexes. Restriction enzymes will be used to probe the specific binding of the platinum complexes; and gel electrophoretic mobility shift assays will be used to determine the unwinding angles that are induced by the coordination of the platinum to plasmid DNA. The new compounds will be tested in a panel of cancer cell lines to examine their cytotoxic activity. Emphasis will be given to test the new compounds in breast and colon cancer cell lines, systems that show intrinsic resistance to cisplatin and to other chemotherapeutic agents. Some of the reported cationic antitumor complexes will be prepared, and their binding to DNA will be studied by Raman spectroscopy. The development of new platinum antitumor drugs is needed to improve the chemotherapeutic approach to cancer treatment.
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