SYNTHESIS OF NUCLEIC ACID AND NUCLEOTIDE METAL COMPLEXES

描述：(逐字摘自申请者摘要)我的目标是定义 金属与核酸相互作用的基本化学原理 核苷酸。最近我们做了一些观察，大大改变了重要的 N7-铂-N7交联鸟嘌呤的顺铂-DNA加合物 Motif。这种有价值的抗癌治疗剂，临床上用于治疗 癌症发病率不断上升，预计将继续发挥重要作用 通向未来。在普遍接受的假设中，蛋白质之间的相互作用 (包括酶)与扭曲的PtDNA启动了生物信息流 导致癌细胞死亡的事件。发现的大量蛋白质可以 与病变的互动造成了对生物学上的缺乏共识 困扰着这一关键领域的机制。此外，全世界都在努力寻找 尽管对3000多种类似药物进行了测试，但一种更好的药物还是失败了 不同的载体配体。我假设两个严肃的生物医学 问题源于对顺铂加合物的认识不足 化学；这种化学很难处理，因为药物的简单性 几乎没有什么办法来阐明这种化学作用。我还假设，非常大的 以DNA GN7-铂-GN7为交联点的快速动态运动 损伤会发生，但研究人员尚未充分认识到这一点。我们测试 这些假设通过一种经过深思熟虑的独特的追溯建模策略来实现 具有载体配体的异构性纯络合物，旨在提供所需的 手柄和减少内收运动。我们已经通过以下方式减缓了动态过程 数十亿倍，从而发现了无数新的N7-铂-N7交联链 铂药物化学的传统方法无法检测到的特性。许多. 这些性质是无法预见的，它们提出了关于 PtDNA化学可能赋予顺铂其非凡的活性。我 建议推进这种反向建模化学来检验几个新的假说 与DNA双链加合物有关，包括(A)存在和可能的 单链区域和新的病变构象的重要性，(B) (C)载体配体NH基团对反应的影响 结构和动力学。我们的方法将产生一类新的合成 作为生物传感器的顺铂类似物；这些生物传感器将携带 DNA聚合物中加合物构象的可识别印迹及其优点 在光谱研究中。此外，我们还将构建稳定的少流 PT-寡核苷酸双链，将作为探测工具 生物机制。我们史无前例的发现具有超越 由于我们正在识别新的核酸，所以抗癌药物的领域 这种不寻常的结构具有的结构和光谱特征。

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.