SYNTHESIS OF NUCLEIC ACID AND NUCLEOTIDE METAL COMPLEXES

金属抗癌药物活性（Pt，Ru）一般为 这是由于DNA交联扭曲了DNA结构 被蛋白质识别。 这样的交联也会导致突变 铂和其他可能的重金属（汞）。 GpG和ApG的5'对 交联，由广泛使用的铂抗- 癌症药物，是独特的扭曲。 这个5'的网站已经很难 因为它的流动性。网站高度 诱变，可能导致长期存活者患癌的因素 药物治疗。 Pt（NH）H-键合到DNA，核碱基取向， 和容易旋转的Pt-碱键的影响的形成， 结构，以及具有活性或 诱变交联。 本提案的目标是阐明和 然后控制这些因素。 实现这些目标将使 研究人员测试了许多与作用机制有关的假设 临床使用的铂类药物;这一知识可能导致设计 上级铂药物在最佳DNA中形成最具活性的加合物 蛋白质结合的构象。 在以前的工作中，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 这种设计的一个概念上的进步是将 环中的Pt（NH）基团同时固定NH取向， 赋予手性。 伴随的大量物质，例如2，2 '-联哌啶 (BiP)络合物限制了Pt-N（核嘌呤）键的旋转。 在 初步研究，这些复合物显示出研究如何 形成交联加合物。 这些知识可能有助于 评估关于（a）PtDNA加合物是否转化 很容易从B-到A-型，一种假设参与蛋白质 加合物的结合和（B）是否是链内或链间类型的 交联导致Pt药物抗癌活性。 最近的一个假设 表明链内交联转化为链间交联， 从长远来看，通过Cl（-）置换，这些物质更具致突变性。 ）;在这项工作中开发的加合物中，这一过程可以减慢 或通过固定加合物中的核碱基取向以掩盖 Pt轴向位置受到亲核攻击。 八面体抗癌 药物比正方形平面Pt药物更不容易形成交联。 如果 抑制交联的因素可以理解，更多类型的 可以设计出金属抗癌药物。 拟采用的方法包括 合成化学、光谱学、凝胶电泳和计算 方法.

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.