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: 3276755
• 负责人: LUIGI G. MARZILLI
• 金额: $ 20.39万
• 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 1995-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3276755
• 关键词: DNA; RNA; Z DNA; adduct; amino group; analytical chemistry; antineoplastics; bleomycin; chemical binding; chemical models; circular dichroism; cobalt; computer graphics /printing; computer simulation; conformation; crosslink; diamines; gel electrophoresis; hydrolysis; iron; ligands; magnesium; mercury; metal complex; molecular stacking; nuclear magnetic resonance spectroscopy; nucleic acid chemical synthesis; nucleobase; oligonucleotides; platinum; rhodium; viscosity; zinc

Overall goals are a) to continue elucidating the nature of nucleic acid binding of metal species, including metal anticancer drugs, and b) to initiate a new approach in the metal nucleic acid field, namely metal stabilization of unusual oligonucleotide conformations useful in advancing our fundamental knowledge of nucleic acid biochemistry and potentially useful, in the long term, as therapeutics. Some of the myriad reasons for the significance of metal nucleic acid interactions include: the presence in or the requirement for metals in widely used DNA-attacking broad spectrum anticancer drugs (e.g.cisplatin, bleomycin (BLM)); the presence of metal species, probably at the active site, of ribozymes; DNA interactions in metal induced mutagenesis or carcinogenesis; the essential role metal ions play in controlling nucleic acid structures, e. g. tRNA, telomeres, Z-DNA, etc.; the ubiquitous involvement of metal ions in nucleotide biochemistry and in nucleic acid binding proteins and processing enzymes, e.g. in transcription factors, reverse transcriptases, etc.; and the growing utility of metalloprobes for nucleic acid structure and biochemistry. Since our knowledge of metal nucleic acid interactions is far from complete, we propose a number of fundamental studies with emphasis on metal-oligonucleotide species, which have received little study by direct methods such as NMR spectroscopy. The few reported studies with direct methods concentrate on Pt compounds. We propose to go further and to design metal-oligonucleotide species in which metal coordination stabilizes the oligonucleotide in an unusual conformation. Emphasis will be placed on hairpin structures in order to establish the principles needed to control structure. In later years, we propose to apply the knowledge gained to develop models of stable hairpin-type DNA/RNA hybrid ribozymes. One can imagine a number of applications of this new approach., e. g. stabilized ribozymes directed against viruses such as HIV-1, stabilized DNA structural components that bind tightly to resistance factors, etc. In laying the foundation for a rational approach to synthesize such structures, we will rely heavily on fundamental principles of coordination chemistry and metal-nucleic acid chemistry. We will use a new concept that we have recently shown to be feasible, namely the stereochemical control of the orientation of NH groups of resolved asymmetric diamine ligands coordinated to Pt(III). Besides the synthetic value of this type of complex, the knowledge gained will increase our understanding of the mode of action of Pt anticancer drugs since the interaction of the NH groups with DNA is essential (Pt compounds lacking NH groups are inactive). In addition, such complexes may induce new types of distorted DNA structures that are not recognized by repair enzymes or resistance factors in cancer cells. Other fundamental studies proposed include evaluating factors that differentiate between nucleobase and phosphate coordination, investigating the structure of metal BLM and tallysomycin complexes and their binding to oligonucleotides, and examining the binding of metal species to B-form DNA and to DNAs with unusual structural features such as bulges or lesions induced by other drugs. These include studies aimed at understanding synergism of Pt drugs with BLM. Methods include multinuclear (31p, 13C, 195pt) NMR/distance geometry methods, CD, molecular mechanics calculations, and gel electrophoresis.

总体目标是 a) 继续阐明核酸的性质 金属物质的结合，包括金属抗癌药物，以及b) 开创了金属核酸领域的新途径，即金属核酸 异常寡核苷酸构象的稳定性可用于 提高我们的核酸生物化学基础知识和 从长远来看，作为治疗药物可能有用。 一些 金属核酸相互作用的重要性有多种原因 包括：广泛使用的金属的存在或要求 DNA 攻击广谱抗癌药物（例如顺铂、博来霉素 (BLM));金属物质的存在，可能在活性位点， 核酶；金属诱导突变中的 DNA 相互作用或 致癌作用；金属离子在控制核酸中发挥重要作用 酸结构，例如g。 tRNA、端粒、Z-DNA等；无处不在的 金属离子参与核苷酸生物化学和核酸 结合蛋白和加工酶，例如在转录因子中， 逆转录酶等；以及金属探针的日益实用 用于核酸结构和生物化学。 自从我们了解 金属核酸相互作用还远未完成，我们提出了一些 重点研究金属寡核苷酸种类的基础研究， 很少通过核磁共振等直接方法进行研究 光谱学。 少数报道的直接方法研究集中在 关于 Pt 化合物。我们建议进一步设计 金属寡核苷酸种类，其中金属配位稳定 具有不寻常构象的寡核苷酸。 重点将放在 发夹结构，以便建立控制所需的原则 结构。 在以后的几年里，我们建议将所获得的知识应用到 开发稳定发夹型 DNA/RNA 杂合核酶模型。 一个可以 想象一下这种新方法的许多应用。 g。稳定的 针对 HIV-1 等病毒、稳定 DNA 的核酶 与阻力因素等紧密结合的结构成分。 为合理的综合方法奠定基础 结构，我们将严重依赖基本原则 配位化学和金属核酸化学。 我们将使用一个 我们最近证明可行的新概念，即 解析的 NH 基团方向的立体化学控制 与 Pt(III) 配位的不对称二胺配体。 除了合成的 此类综合体的价值，所获得的知识将增加我们的 自20世纪90年代以来，人们对Pt抗癌药物作用机制的认识 NH 基团与 DNA 的相互作用至关重要（缺乏 Pt 化合物） NH 基团不活跃）。 此外，此类复合物可能会诱导新的 修复无法识别的扭曲 DNA 结构类型 癌细胞中的酶或抵抗因子。 其他基础研究 提议包括评估区分核碱基的因素 和磷酸盐配位，研究金属 BLM 的结构和 他霉素复合物及其与寡核苷酸的结合，以及 检查金属物质与 B 型 DNA 和 DNA 的结合 不寻常的结构特征，例如由其他原因引起的凸起或病变 药物。 其中包括旨在了解 Pt 协同作用的研究 具有 BLM 的药物。 方法包括多核（31p、13C、195pt） NMR/距离几何方法、CD、分子力学计算，以及 凝胶电泳。