SYNTHESIS OF NUCLEIC ACID AND NUCLEOTIDE METAL COMPLEXES

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Recently, the significance of metal-nucleic acid interactions has greatly increased with: a) the broad clinical benefit of Pt anti-cancer compounds which act by attacking DNA; b) the growing number of metal anti-cancer compounds which may act on DNA; c) the synergistic mechanism of action between organic anti-cancer drugs and redox metal centers; d) the development of useful metallo-bioprobes for nucleic acid structure and sequence; e) the identification of Zn-proteins which regulate genes by direct DNA binding; f) the discovery of even more Zn enzymes involved in genetic information transfer; g) the continued identification of metal-DNA interactions in disease, possibly even Alzheimer's disease; h) the mounting evidence that DNA-metal binding may influence expression of genes for metal regulatory and storage proteins; and i) the high propensity for some metal species to induce B yield Z DNA transformation combined with the implied importance of Z DNA both in metal toxicity and gene expression. Our use of synthetic chemistry (synthesis of both metal compounds and nucleic acid components) combined with physical methods has been extended beyond the monomer level to oligodeoxyribonucleotides (up to 16-mer duplexes) and to DNA and synthetic polynucleotides (both deoxy and ribo). I propose to continue to study these larger species with additional synthetic approaches and to extend the types of physical methods we use. Thus, I propose to synthesize nucleosides which either alter or limit the metal binding sites or which contain useful isotopes (13C, 15N, etc.). These will be incorporated into oligodeoxyribonucleotides, some of which will have 17O- and 18O-labeled phosphate groups. The metal binding to DNA, synthetic polynucleotides and normal or modified oligodeoxyribonucleotides will be studied by a battery of techniques including multinuclear NMR spectroscopy (1H, 31P, 195Pt, 113Cd, etc.; 2D NOE absorption mode; solvent suppression; heteronuclear multiquantum coherences, etc.), other types of spectroscopy (CD, Raman), and, where applicable, viscosity, melting studies, and flow dichroism. Specific systems include: cationic porphyrin complexes as probes of DNA structure and flexibility; Pt anti-cancer compounds and other Pt and related Pd compounds as a means of a) relating spectral changes, particularly 31P NMR spectral changes, to binding mode and b) gaining insight into factors which influence rates of reaction and hence selectivity of metal centers; the relationship of 113Cd NMR shifts to nucleic acid binding sites; the DNA binding mode of cancer drugs bound to inert metals (Co(III) and Pt(II)) - such complexes can model those with metals (Fe(III), Cu(II)) believed to act synergistically with anti-cancer drugs such as bleomycin; and the binding of toxic metal ions and metal alkyls (Hg, Pb) to DNA. The information gained could be useful in developing better cancer treatments, avoiding or minimizing the effects of toxic metals, and in gaining a better understanding of the role of metals in genetic information transfer.