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

DNA 结合剂中的糖——结构、功能和设计

• 批准号: 2408040
• 负责人: Daniel Kahne
• 金额: $ 31.54万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-05-01 至 2001-06-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2408040
• 关键词: DNA; anthracyclines; antineoplastic antibiotics; carbohydrate structure; chemical binding; chemical models; chemical structure function; circular dichroism; drug design /synthesis /production; metal complex; nuclear magnetic resonance spectroscopy; oligosaccharides; spectrometry; ultraviolet spectrometry

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.

描述：拟议研究的目标是了解 三个不同家族的结构和功能之间的关系 糖基化的抗肿瘤抗生素，通过研究来自 每个家庭。 选择的分子，加利车霉素，色霉素，和 阿克拉霉素与DNA结合并含有已知的碳水化合物部分， 对活动至关重要。 然而，它们具有不同的机制 的行动。 更好地理解结构和功能之间的关系 在这些分子中， 剂. 拟议的目标包括两种类型的实验： 了解天然产品本身的功能;以及 那些针对合成和评估天然的类似物的 产品基于关于结构特征重要性的假设。 重点将放在碳水化合物的作用。 1. 加利车霉素：加利车霉素是一种烯-二炔类抗肿瘤抗生素， 结合并切割DNA。 加利车霉素的寡糖尾部是 主要的DNA结合元件。 为了了解更多关于 加利车霉素寡糖识别DNA，将合成类似物 并评价它们的结合性能。 类似物的设计将是 基于一系列核磁共振结构，这导致了一个假设， 实现了结合选择性。 二. 色霉素A3：色霉素A3（CRA 3）是一种金酸类抗肿瘤药物， 与Mg 2+形成非对映异构体2：1复合物的抗生素。 这 二聚体复合物与DNA结合并抑制DNA和RNA聚合酶。 的 CRA 3的三糖侧链在组织细胞中起着关键作用。 非对映异构Mg ~（2+）配合物。 为了了解更多关于结构 二聚体形成和DNA结合的要求，类似物将被 综合和评估。 控制金属形状的能力 使用非共价相互作用的复合物可以很好地应用于 除了设计具有潜在抗肿瘤活性的新DNA结合剂之外。 三. 阿克拉霉素：阿克拉霉素是一种蒽环类抗肿瘤抗生素 与DNA结合，还抑制拓扑异构酶活性。 的 三糖在拓扑异构酶抑制中起关键作用。 阐明拓扑异构酶抑制机制的实验是 提出了