SYNTHESIS OF NUCLEIC ACID AND NUCLEOTIDE METAL COMPLEXES

近年来，金属-核酸相互作用的重要性大大提高， 增加：a）铂抗癌化合物的广泛临床获益 通过攻击DNA起作用; B）越来越多的金属抗癌 可能作用于DNA的化合物; c）协同作用机制 有机抗癌药物和氧化还原金属中心之间的相互作用; d） 开发了用于核酸结构的有用的金属生物探针， 序列; e）鉴定锌蛋白，其通过以下方式调节基因： 直接DNA结合; f）发现更多的锌酶参与 遗传信息转移; g）金属DNA的持续鉴定 疾病的相互作用，甚至可能是阿尔茨海默病; h） DNA-金属结合可能影响金属基因表达的证据 调节和储存蛋白质;和i）对某些金属的高倾向性 种诱导B产量Z DNA转化结合暗示 Z DNA在金属毒性和基因表达中重要性。 我们使用合成化学（金属化合物和 核酸组分）与物理方法相结合的方法已经被扩展 超过单体水平至寡脱氧核糖核苷酸（高达16-mer 双链体）以及DNA和合成多核苷酸（脱氧和核糖）。 我建议继续研究这些较大的物种， 综合方法和扩展我们使用的物理方法的类型。 因此，我建议合成核苷，改变或限制 金属结合位点或含有有用的同位素（13 C、15 N等）。 这些将被掺入寡脱氧核糖核苷酸，其中一些 都有17 O和18 O标记的磷酸基团。 与DNA结合的金属， 合成的多核苷酸和正常的或修饰的寡脱氧核糖核苷酸 将通过一系列技术进行研究，包括多核核磁共振 光谱学（1H、31 P、195 Pt、113 Cd等; 2D NOE吸收模式;溶剂 抑制;异质多量子相干等），其他类型的 光谱（CD，拉曼），以及适用的粘度，熔融 研究和流动二色性。 具体的体系包括：阳离子卟啉配合物作为DNA的探针 结构和柔性; Pt抗癌化合物和其它Pt和 相关Pd化合物作为a）相关光谱变化的手段， 特别是31 P NMR光谱变化，结合模式和B）获得 深入了解影响反应速率的因素， 金属中心的选择性; 113 Cd NMR位移与 核酸结合位点;癌症药物的DNA结合模式结合到 惰性金属（Co（III）和Pt（II））-这样的络合物可以模拟那些具有 金属（Fe（III），Cu（II））被认为与抗癌协同作用 药物如博来霉素;以及有毒金属离子和金属 烷基（Hg，Pb）与DNA的相互作用。 获得的信息可能会很有用， 开发更好的癌症治疗方法，避免或尽量减少 有毒金属，以及更好地了解金属的作用 基因信息转移。

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.