SUGARS IN DNA BINDERS--STRUCTURE, FUNCTION, AND DESIGN

描述：拟议研究的目标是了解 三个不同家系的结构与功能的关系 糖基化抗肿瘤抗生素的研究 每个家庭。所选分子，Calicheamicin，chroomycin，和 阿克拉霉素，与DNA结合，含有已知的碳水化合物部分 对活动来说是必不可少的。然而，它们有不同的机制。 行动的一部分。更好地理解结构和功能之间的关系 这些分子可能导致设计出更好的抗肿瘤药物的能力 探员们。拟议的目标包括两种类型的实验：定向实验 了解自然产品本身的功能；以及 旨在合成和评估天然的类似物 基于关于哪些结构特征重要的假设的产品。 重点将放在碳水化合物的作用上。1. Calicheamicin：Calicheamicin是一种烯-二炔类抗肿瘤抗生素 结合并切割DNA。Calicheamicin的低聚糖尾巴是 主要的DNA结合元件。为了更多地了解 Calicheamicin寡糖识别DNA，将合成类似物 并对它们的结合属性进行评估。类似物的设计将是 基于一系列的核磁共振结构，这些结构导致了一个假说 实现了结合的选择性。 二、铬霉素A3：铬霉素A3(CRA3)是一种金黄色抗癌药物 与镁离子形成非对映异构体2：1络合物的抗生素。这 二聚体与DNA结合，抑制DNA和RNA聚合酶。这个 CRA3的三糖侧链在组织 非对映异构体镁离子络合物。为了了解更多关于结构的知识 二聚体形成和DNA结合的要求，类似物将是 综合评价。控制金属形状的能力 使用非共价相互作用的络合物可能会有很好的应用 除了设计具有潜在抗肿瘤活性的新DNA结合剂外。 阿克拉霉素：阿克拉霉素是一种蒽环类抗肿瘤抗生素 它能与DNA结合，也能抑制拓扑异构酶的活性。这个 三糖在拓扑异构酶抑制中起着关键作用。 阐明拓扑异构酶抑制机制的实验是 建议。

DESCRIPTION: The goal of the proposed research is to understand the relationship between structure and function in three different families of glycosylated antitumor antibiotics by studying a prototypical molecule from each family. The selected molecules, calicheamicin, chromomycin, and aclacinomycin, bind to DNA and contain carbohydrate moieties that are known to be essential for activity. Nevertheless, they have different mechanisms of action. A better understanding of how structure and function are related in thee molecules could lead to the ability to design better antitumor agents. The proposed aims include two types of experiments: those directed towards understanding how the natural products themselves function; and those directed towards synthesizing and evaluating analogues of the natural products based on hypotheses about which structural features are important. Emphasis will be placed on the role of the carbohydrates. 1. Calicheamicin: Calicheamicin is an ene-diyne antitumor antibiotic that binds to and cleaves DNA. The oligosaccharide tail of calicheamicin is the principal DNA binding element. In order to learn more about how the calicheamicin oligosaccharide recognizes DNA, analogues will be synthesized and their binding properties evaluated. The design of the analogues will be based on a series of NMR structures which have led to a hypothesis for how binding selectivity is achieved. II. Chromomycin A3: Chromomycin A3 (CRA3) is an aureolic acid antitumor antibiotic that forms a diastereoisomeric 2:1 complex with Mg2+. This dimeric complex binds to DNA and inhibits DNA and RNA polymerases. The trisaccharide side chain of CRA3 plays a key role in organizing the diasteroisomeric Mg2+ complex. In order to learn more about the structural requirements for dimer formation and DNA binding, analogues will be synthesized and evaluated. The ability to control the shape of metal complexes using non-covalent interactions could have applications well beyond the design of new DNA binders with potential antitumor activity. III. Aclacinomycin: Aclacinomycin is an anthracycline antitumor antibiotic that binds to DNA It also inhibits topoisomerase activity. The trisaccharide plays a critical role in topoisomerase inhibition. Experiments to elucidate the mechanism of topoisomerase inhibition are proposed.