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: 6129343
• 负责人: LUIGI G. MARZILLI
• 金额: $ 25.74万
• 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 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6129343
• 关键词: antineoplastics; bleomycin; chemical binding; circular dichroism; cobalt; computer simulation; crosslink; drug design /synthesis /production; drug interactions; gel electrophoresis; high performance liquid chromatography; magnesium; matrix assisted laser desorption ionization; mercury; metal complex; nuclear magnetic resonance spectroscopy; nucleic acid chemical synthesis; nucleic acid structure; nucleotides; oligonucleotides; platinum; rhodium; zinc

DESCRIPTION: (verbatim from applicant's abstract) My aim is to define the fundamental chemical principles of metal interactions with nucleic acids and nucleotides. Recently we have made observations that greatly alter important concepts about cisplatin-DNA adducts with guanines cross-linked by an N7-Pt-N7 motif. This valuable anticancer therapeutic agent, used clinically for treating cancers with growing incidence, is predicted to have continued importance well into the future. In the generally accepted hypothesis, interaction of proteins (including enzymes) with the distorted PtDNA initiates the stream of biological events causing cancer cell death. The large number of proteins found to interact with the lesion has created a lack of consensus on the biological mechanism that plagues this crucial field. Also, the world-wide effort to find a superior drug has failed, despite the testing of over 3,000 analogues differing in the carrier ligands. I hypothesize that both serious biomedical problems result from an inadequate understanding of the cisplatin adduct chemistry; this chemistry is intractable because the drug's simplicity affords few handles for elucidating the chemistry. I also hypothesize that very large and rapid dynamic motions centered at the Pt of DNA GN7-Pt-GN7 cross-link lesions occur but have not been appreciated fully by investigators. We test these hypotheses through a deliberate unique retro-modeling strategy using isomerically pure complexes with carrier ligands designed to provide the needed handles and to decrease adduct motion. We have slowed the dynamic processes by a billion-fold, thereby uncovering numerous novel N7-Pt-N7 cross-link properties undetectable by traditional approaches to Pt drug chemistry. Many of these properties could not have been foreseen, and they raise hypotheses about the PtDNA chemistry that might bestow on cisplatin its remarkable activity. I propose to advance this retro-modeling chemistry to test several new hypotheses relating to DNA duplex adducts, including (a) the existence and possible importance of single-stranded regions and novel lesion conformers, (b) the formation of cross-links, and (c) the influence of carrier ligand NH groups on structure and dynamics. Our approach will yield a new class of synthetic cisplatin analogs acting as biosensors; these biosensors will bear an identifiable imprint of adduct conformation in DNA polymers and have advantages in spectroscopic studies. Also, we will construct stable less fluxional Pt-oligonucleotide duplexes, which will be available as tools for probing biological mechanisms. Our unprecedented findings have significance beyond the field of anticancer drugs since we are identifying novel nucleic acid structures and the spectroscopic signatures such unusual structures possess.

描述：（逐字研究申请人的摘要）我的目的是定义 金属与核酸和金属相互作用的基本化学原理和 核苷酸。最近，我们进行了观察，这些观察极大地改变了 关于顺铂DNA加合物的概念，与N7-PT-N7交联的鸟嘌呤 主题。这种有价值的抗癌治疗剂在临床上用于治疗 预计发病率不断增长的癌症持续很重要 进入未来。在普遍接受的假设中，蛋白质的相互作用 （包括酶）随着扭曲的ptDNA启动生物流 导致癌细胞死亡的事件。发现大量蛋白质 与病变的互动使生物学缺乏共识 困扰着这个关键领域的机制。此外，全球努力寻找 尽管测试了3,000多个类似物，但一种上级药物还是失败了 载体配体不同。我假设两者都是认真的生物医学 对顺铂加合物的理解不足导致问题 化学;这种化学是棘手的，因为该药物的简单性提供了 很少有用于阐明化学的手柄。我也假设这很大 以及以DNA GN7-PT-GN7交联的PT为中心的快速动态运动 研究人员发生了病变但尚未完全理解。我们测试 这些假设通过使用故意的独特的复古模型策略使用 载载配体的同构纯络合物，旨在提供所需的 处理并降低加合物运动。我们通过 十亿倍，从而发现了许多新颖的N7-PT-N7交叉链接 通过传统的PT药物化学方法无法检测到的特性。许多 这些属性无法预见，它们提出了有关的假设 PTDNA化学可能会赋予顺铂其出色活性。我 建议推进这种复古模型化学以检验几个新假设 与DNA双链合并有关，包括（a）存在和可能 单链区域和新型病变构象体的重要性，（b） 交联的形成，（c）载体配体NH组对 结构和动态。我们的方法将产生新的合成类 顺铂类似物作为生物传感器；这些生物传感器将带有 DNA聚合物中可识别的加合构象的烙印，并具有优势 在光谱研究中。另外，我们将构造稳定的量不足 PT-寡核苷酸双工，将作为探测工具可用 生物学机制。我们空前的发现超出了 抗癌药物领域，因为我们正在识别新型核酸 结构和光谱特征具有这种异常结构。