SYNTHESIS OF NUCLEIC ACID AND NUCLEOTIDE METAL COMPLEXES

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Overall goals are a) to continue elucidating the nature of nucleic acid binding of metal species, including metal anticancer drugs, and b) to initiate a new approach in the metal nucleic acid field, namely metal stabilization of unusual oligonucleotide conformations useful in advancing our fundamental knowledge of nucleic acid biochemistry and potentially useful, in the long term, as therapeutics. Some of the myriad reasons for the significance of metal nucleic acid interactions include: the presence in or the requirement for metals in widely used DNA-attacking broad spectrum anticancer drugs (e.g.cisplatin, bleomycin (BLM)); the presence of metal species, probably at the active site, of ribozymes; DNA interactions in metal induced mutagenesis or carcinogenesis; the essential role metal ions play in controlling nucleic acid structures, e. g. tRNA, telomeres, Z-DNA, etc.; the ubiquitous involvement of metal ions in nucleotide biochemistry and in nucleic acid binding proteins and processing enzymes, e.g. in transcription factors, reverse transcriptases, etc.; and the growing utility of metalloprobes for nucleic acid structure and biochemistry. Since our knowledge of metal nucleic acid interactions is far from complete, we propose a number of fundamental studies with emphasis on metal-oligonucleotide species, which have received little study by direct methods such as NMR spectroscopy. The few reported studies with direct methods concentrate on Pt compounds. We propose to go further and to design metal-oligonucleotide species in which metal coordination stabilizes the oligonucleotide in an unusual conformation. Emphasis will be placed on hairpin structures in order to establish the principles needed to control structure. In later years, we propose to apply the knowledge gained to develop models of stable hairpin-type DNA/RNA hybrid ribozymes. One can imagine a number of applications of this new approach., e. g. stabilized ribozymes directed against viruses such as HIV-1, stabilized DNA structural components that bind tightly to resistance factors, etc. In laying the foundation for a rational approach to synthesize such structures, we will rely heavily on fundamental principles of coordination chemistry and metal-nucleic acid chemistry. We will use a new concept that we have recently shown to be feasible, namely the stereochemical control of the orientation of NH groups of resolved asymmetric diamine ligands coordinated to Pt(III). Besides the synthetic value of this type of complex, the knowledge gained will increase our understanding of the mode of action of Pt anticancer drugs since the interaction of the NH groups with DNA is essential (Pt compounds lacking NH groups are inactive). In addition, such complexes may induce new types of distorted DNA structures that are not recognized by repair enzymes or resistance factors in cancer cells. Other fundamental studies proposed include evaluating factors that differentiate between nucleobase and phosphate coordination, investigating the structure of metal BLM and tallysomycin complexes and their binding to oligonucleotides, and examining the binding of metal species to B-form DNA and to DNAs with unusual structural features such as bulges or lesions induced by other drugs. These include studies aimed at understanding synergism of Pt drugs with BLM. Methods include multinuclear (31p, 13C, 195pt) NMR/distance geometry methods, CD, molecular mechanics calculations, and gel electrophoresis.