SYNTHESIS OF NUCLEIC ACID AND NUCLEOTIDE METAL COMPLEXES

近年来，金属-核酸相互作用的意义越来越大。 增加：a)铂抗癌化合物的广泛临床益处 它们通过攻击DNA来发挥作用；b)越来越多的金属抗癌药物 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关系； 实用的核酸结构金属生物探针的研制 序列；e)鉴定锌蛋白，锌蛋白通过 直接DNA结合；f)发现更多的锌酶参与 遗传信息传递；g)金属DNA的持续鉴定 疾病中的相互作用，甚至可能是阿尔茨海默氏症；h)不断增加的 DNA与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；以及i)某些金属的高倾向性 诱导B产量Z DNA转化的物种与隐含的 Z DNA在金属毒性和基因表达中的重要性。 我们对合成化学的使用(金属化合物的合成和 核酸成分)与物理方法相结合的方法已扩展 从单体水平到寡聚脱氧核糖核苷酸(最多16聚体 双链)以及DNA和合成多核苷酸(脱氧和核糖核酸)。 我建议继续研究这些较大的物种，另外 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，它可以改变或限制 金属结合部位或含有有用的同位素(13C、15N等)。 这些将被加入到寡聚脱氧核糖核苷酸中，其中一些 将具有17O和18O标记的磷酸基团。金属与DNA的结合， 合成多核苷酸和正常或修饰的寡核苷酸 将通过包括多核核磁共振在内的一系列技术进行研究 光谱(1H、31P、195Pt、113Cd等；二维NOE吸收模式；溶剂 抑制；异核多量子相干等)、其他类型的 光谱(Cd、拉曼)，如果适用，还包括粘度、熔融 研究和流动二向色性。 具体的体系包括：作为DNA探针的阳离子卟啉配合物 结构和柔韧性；铂抗癌化合物和其他铂和 相关Pd化合物作为a)关联光谱变化的手段， 特别是~(31)P核磁共振谱变化到结合模式，以及b)获得 洞察影响反应速度的因素，从而了解 金属中心的选择性；~(113)Cd核磁共振的关系向 核酸结合部位；抗癌药物结合DNA的模式 惰性金属(钴(III)和铂(II))-这类络合物可以模拟 被认为具有抗癌协同作用的金属(Fe(III)，Cu(II)) 博莱霉素等药物；有毒金属离子与金属的结合 烷基(汞，铅)到DNA。所获得的信息可能对 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 在遗传信息传输中。

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.