SYNTHESIS OF NUCLEIC ACID AND NUCLEOTIDE METAL COMPLEXES

核酸和核苷酸金属复合物的合成

• 批准号: 3276760
• 负责人: LUIGI G. MARZILLI
• 金额: $ 18.57万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-09-01 至 1991-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3276760
• 关键词: DNA binding protein; Raman spectrometry; X ray crystallography; analytical chemistry; antineoplastics; antirheumatic agents; calcium; chemical binding; chemical models; chemical structure; chemical synthesis; guanosine; ligands; magnesium; metal complex; metal poisoning; metalloenzyme; molecular energy level; molecular stacking; nuclear magnetic resonance spectroscopy; nucleic acid biosynthesis; nucleic acid chemical synthesis; nucleic acid sequence; nucleobase; platinum; potassium; protonation; purines; pyrimidines; reagent /indicator; sodium; stereochemistry

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.

最近，金属核酸相互作用的重要性大大具有 增加：a）PT抗癌化合物的广泛临床益处 攻击DNA的作用； b）金属抗癌的数量越来越多 可能作用于DNA的化合物； c）作用的协同机制 在有机抗癌药物和氧化还原金属中心之间； d） 开发用于核酸结构和 顺序; e）鉴定Zn-蛋白质，这些蛋白通过 直接DNA结合； f）发现更多参与的锌酶 遗传信息转移； g）持续识别金属-DNA 疾病的相互作用，甚至可能是阿尔茨海默氏病； h）安装 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； i）某些金属的高倾向 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。 我们使用合成化学（金属化合物的合成和 核酸成分）与物理方法结合了 超出单体水平到寡脱毛核苷酸（最多16-mer） 双链体）以及DNA和合成多核苷酸（脱氧和Ribo）。 我建议继续研究这些较大的物种 合成方法并扩展我们使用的物理方法的类型。 因此，我建议合成改变或限制的核苷 金属结合位点或包含有用的同位素（13C，15N等）。 这些将被掺入寡脱氧核糖核苷酸中，其中一些 将具有17o和18o标记的磷酸基团。 金属与DNA结合， 合成多核苷酸和正常或改良的寡脱毛核苷酸核苷酸 将通过包括多核NMR在内的一系列技术进行研究 光谱法（1H，31p，195pt，113cd等； 2D NOE吸收模式；溶剂 抑制;杂核多Quantum相干等），其他类型的 光谱法（CD，拉曼），以及适用的粘度，融化 研究和流动二分性能。 特定系统包括：阳离子卟啉复合物作为DNA的探针 结构和灵活性； PT抗癌化合物和其他PT和 相关的PD化合物作为a）与光谱变化相关的一种手段， 特别是31p 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； 113CD NMR的关系转移到 核酸结合位点；癌症药物的DNA结合模式与 惰性金属（CO（iii）和Pt（ii）） - 此类复合物可以建模 金属（Fe（iii），Cu（ii））被认为与抗癌者协同作用 博来霉素等药物；以及有毒金属离子和金属的结合 烷基（Hg，Pb）至DNA。 获得的信息可能很有用 开发更好的癌症治疗，避免或最小化 有毒金属，并更好地了解金属的作用 在遗传信息转移中。