CYCLOMETALLATED DNA NUCLEASES

环金属化 DNA 核酸酶

• 批准号: 3296750
• 负责人: JOHN W SUGGS
• 金额: $ 10.3万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-02-01 至 1991-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3296750
• 关键词: DNA; antineoplastics; binding proteins; bleomycin; chemical cleavage; cis platinum compound; drug design /synthesis /production; drug screening /evaluation; hydrogen peroxide; lenticular nucleus; ligands; mass spectrometry; metal complex; nuclear magnetic resonance spectroscopy; nuclease; oncogenes; ultraviolet spectrometry

Numerous transition metal complexes have been used as drugs, especially as anti-cancer agents Cisplatin and bleomycin are two examples of drugs which contain a transition metal (platinum and iron, respectively) and both of these are important chemotherapy agents. These drugs, as well as most other anti-cancer drugs, have as their cellular target DNA. Recently, it has been discovered that a new palladium complex (formed by the cyclometallation of PdCl2 with the chelating organic ligand 2'-(2- methoxyphenyl) 1,10phenanthroline) will, in the presence of an oxidant such as hydrogen peroxide, specifically nick DNA at dG residues. Hydrog peroxide alone or in combination with simple palladium salts does not exhibit this specificity. The palladium complex possesses structural features in common with both the Cisplatin group of drugs and with intercalators. Nevertheless, it has novel features, such as a transition-metal carbon bond. One of the goals of this research will be to see if the Pd-C bond is in any way responsible for the palladium complex's DNA nicking activity. The immediate goal of the project will be to determine the chemistry of DNA strand scission produced by the palladium complex. Chromatographic techniques will be used to isolate the strand cleavage products and UV, NMR and mass spectroscopy to identify the chemical residues released upon DNA nicking. An attempt will be made to grow crystals of the palladium nuclease and DNA oligomers, including the dinucleotide d(CpG) in order to understand exactly how the complex binds to DNA. Binding constants and unwinding angles will also be measured in order to characterize the Pd complex-DNA adduct. Finally, structural modifications will be made to the complex in order to increase its DNA binding and cleavage specificity. The Pd complex seems to bind in or through the DNA major groove. It thus should serve as a platform on which other molecules could be attached. Most DNA binding proteins and enzymes which process DNA (such as restriction enzymes and repressor molecules) bind in the DNA major groove and molecules which mimic these enzymes (based on the structure of the palladium metallocycle) will be prepared. The long range goal of this project is to understand how small molecules bind to DNA in order to design and synthesize new DNA binding drugs and also to mimic the properties of some DNA binding proteins. The ability to make synthetic repressor molecules which would bind to specific genes (including oncogenes) for example, would have widespread use in biotechnology and medicine.

许多过渡金属配合物已被用作药物， 尤其是作为抗癌药物顺铂和博莱霉素是两种 含有过渡金属（铂和 铁，分别），这两者都是重要的化疗 代理。 这些药物以及大多数其他抗癌药物， 有作为他们的细胞目标DNA。 最近，已经 发现了一种新的钯络合物（由 PdCl2 与螯合有机配体 2'-(2- 甲氧基苯基）1,10菲咯啉）会，在存在的情况下 氧化剂，例如过氧化氢，特别是 dG 处的切口 DNA 残留物。 单独使用过氧化氢或与简单的组合 钯盐不表现出这种特异性。 钯金 复合物具有与两者共同的结构特征 顺铂组药物和嵌入剂。 尽管如此，它 具有新颖的特征，例如过渡金属碳键。 一 这项研究的目标之一是看看 Pd-C 键是否处于 钯配合物 DNA 切口的任何方式 活动。 该项目的近期目标是确定 钯产生的 DNA 链断裂的化学反应 复杂的。 色谱技术将用于分离 链断裂产物以及 UV、NMR 和质谱分析 识别 DNA 切口时释放的化学残留物。 一个 将尝试生长钯核酸酶晶体 和 DNA 寡聚物，包括二核苷酸 d(CpG)，以便 准确了解复合物如何与 DNA 结合。 装订 还将测量常数和展开角度，以便 表征 Pd 复合物-DNA 加合物。 最后，将对综合体进行结构修改 以增加其 DNA 结合和切割特异性。 这 Pd 复合物似乎结合在 DNA 大沟中或通过 DNA 大沟结合。 它 因此应该作为其他分子可以在其上进行的平台 随附的。 大多数 DNA 结合蛋白和酶可处理 DNA（例如限制酶和阻遏分子）结合在 DNA大沟和模仿这些酶的分子 （基于钯金属环的结构）将是 准备好了。 该项目的长期目标是了解如何 小分子与 DNA 结合以设计和合成 新的 DNA 结合药物以及模仿某些药物的特性 DNA 结合蛋白。 制造合成阻遏物的能力 与特定基因结合的分子（包括 癌基因）例如，将广泛用于 生物技术和医学。