SYNTHESIS OF NUCLEIC ACID AND NUCLEOTIDE METAL COMPLEXES

核酸和核苷酸金属复合物的合成

基本信息

批准号：
2749797
负责人：
LUIGI G. MARZILLI
金额：
$ 27.38万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1980
资助国家：
美国
起止时间：
1980-09-01 至 2000-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2749797
关键词：
bleomycin chemical binding cobalt computer simulation crosslink gel electrophoresis hydrolysis magnesium mercury metal complex nuclear magnetic resonance spectroscopy nucleic acid chemical synthesis nucleotides oligonucleotides platinum rhodium zinc

项目摘要

DESCRIPTION: Metal anti-cancer drug activity (Pt, Ru) is generally attributed to DNA cross-linking which distorts the DNA structure in ways that are recognized by proteins. Such cross-links also cause mutations by Pt and possibly other heavy metals (Hg). The 5' pair of GpG and ApG cross-links, the major DNA lesions caused by the widely used Pt anti- cancer drugs, is uniquely distorted. This 5' site has been difficult to characterize because of its fluxional nature. The site is highly mutagenic, a factor likely contributing to cancer in long-term survivors of drug treatment. Pt(NH) H-bonding to the DNA, nucleobase orientation, and ease of rotation about the Pt-base bond influence the formation, the structure, and the fluxionality of the DNA adducts with active or mutagenic cross-links. The goals of this proposal are to elucidate and then control these factors. Achieving these goals would allow investigators to test many hypotheses related to the mechanism of action of clinically used Pt drugs; this knowledge could lead to the design of superior Pt drugs forming the most active adducts in the optimal DNA conformation for protein binding. In previous work, the PI has designed and initiated investigations into new Pt(diamine)X(2) complexes for assessing and controlling structure and fluxional properties of PtDNA adducts. A conceptual advance in this design is the incorporation of the Pt(NH) groups in rings which simultaneously fix NH orientation and impart chirality. The attendant bulk, for example of 2,2'-bipiperidine (BiP) complex limits rotation about the Pt-N(nucleopurine) bond. In preliminary studies, these complexes show promise for investigating how cross-linked adducts are formed. Such knowledge may be helpful in assessing the controversies concerning (a) whether PtDNA adducts convert readily from B- to A-form, a form hypothesized to be involved in protein binding of adducts and (b) whether the intra- or inter-strand type of cross-link leads to Pt drug anti-cancer activity. A recent hypothesis suggests intrastrand cross-links convert to interstrand cross-links, and these are more mutagenic in the long-term, through displacement by Cl(- ); in the adducts developed in this work, this process could be slowed or eliminated by fixing nucleobase orientation in the adducts to obscure the Pt axial sites from nucleophilic attack. Octahedral anti-cancer drugs form cross-links less readily than square planar Pt drugs. If factors inhibiting cross-links can be understood, many more types of metal anti-cancer drugs could be designed. Approaches to be used include synthetic chemistry, spectroscopy, gel electrophoresis, and computational methods.

描述：金属抗癌药物活性（Pt、Ru）一般为归因于 DNA 交联，它以某种方式扭曲了 DNA 结构被蛋白质识别的。这种交联也会引起突变由 Pt 和可能的其他重金属 (Hg) 引起。 5' 对 GpG 和 ApG 交联是广泛使用的 Pt 抗-DNA 引起的主要 DNA 损伤抗癌药物，被独特地扭曲了。这个 5' 站点很困难由于其流动性而被表征。该网站的评价很高诱变，可能导致长期幸存者罹患癌症的一个因素的药物治疗。 Pt(NH) 与 DNA 形成氢键，核碱基方向，和绕 Pt 基键旋转的难易程度影响形成，结构，以及具有活性或活性的DNA加合物的流动性诱变交联。该提案的目标是阐明和然后控制这些因素。实现这些目标将允许研究人员测试与作用机制相关的许多假设临床使用的铂类药物；这些知识可能导致设计优质 Pt 药物在最佳 DNA 中形成最活跃的加合物蛋白质结合的构象。在之前的工作中，PI 设计了并开始研究新的 Pt(二胺)X(2) 配合物评估和控制 PtDNA 的结构和流动特性加合物。该设计的一个概念性进步是结合了环中的 Pt(NH) 基团同时固定 NH 方向和赋予手性。伴随的大量物质，例如 2,2'-联哌啶 (BiP) 络合物限制 Pt-N（核嘌呤）键的旋转。在初步研究表明，这些复合物有望研究如何形成交联加合物。这些知识可能会有所帮助评估关于 (a) PtDNA 加合物是否转化的争议很容易从 B 型转变为 A 型，一种推测与蛋白质有关的形式加合物的结合以及（b）加合物是链内还是链间类型交联导致铂药物抗癌活性。最近的一个假设建议链内交联转化为链间交联，并且从长远来看，通过 Cl(- ）；在这项工作中开发的加合物中，这个过程可能会减慢或通过固定加合物中的核碱基方向来消除以掩盖来自亲核攻击的 Pt 轴向位点。八面体抗癌药物比方形平面铂药物更不易形成交联。如果可以理解抑制交联的因素，还有更多类型可以设计金属抗癌药物。使用的方法包括合成化学、光谱学、凝胶电泳和计算方法。