SPECIFICITY OF INTERCALATION REACTIONS

拟议研究的长期目标是了解 分子详细的序列和构象特异性， 涉及临床重要抗生素的嵌入反应。 预计在拟议中获得的信息 研究将直接用于新的合理设计， 插入具有增强的效力和特异性的药物。 的 临床上重要的蒽环类抗生素和一系列新的 将研究蒽吡唑类抗生素。 定量 将采用脱氧核糖核酸酶足迹法， 利用获得微观结合常数描述 这些化合物与特异性DNA结合的相互作用。 将采用停流和温度跃变动力学方法 为了获得用于制定可预测反应的数据， 一种描述抗生素分子 发现并与其特异性DNA结合位点相互作用。 脱氧核糖核酸酶足迹和光谱方法将是 用于检查嵌入剂与B-Z的相互作用 DNA中的连接和弯曲，以观察这些区域是否 用于嵌入药物的高亲和力结合位点。 机械论 嵌入剂作为DNA变构效应物的研究 构象将继续，强调动力学研究的 嵌入剂对DNA中B到Z转变的影响。 的 基础热力学和动力学的相互作用， 一系列新的含DNA的蒽吡唑类抗生素将成为 考察 这些研究的综合结果将提供 了解嵌入的基本细节 过程，一个重要的反应，许多临床上有用的 抗生素与它们的主要细胞靶DNA相互作用。

The long-range goal of the proposed research is to understand in molecular detail the sequence and conformational specificity of intercalcation reactions involving clinically important antibiotics. It is anticipated that information obtained in the proposed research will be of direct use in the rational design of new intercalating drugs with enhanced potency and specificity. The clinically important anthracycline antibiotics and a series of novel anthrapyrazole antibiotics will be studied. A quantitative deoxyribonuclease footprinting method will be implemented and exploited to obtain microscopic binding constants describing the interaction of these compounds with specific DNA binding. Stopped-flow and temperature-jump kinetic methods will be used to obtain data of use toward formulating a pluasible reaction mechanism describing the process by which an antibiotic molecule finds and interacts with its specific DNA binding site. Deoxyribonuclease footprinting and spectroscopic methods will be used to examine the interaction of intercalators with B-Z junctions and bends in DNA, in order to see if such regions are high affinity binding sites for intercalating drugs. Mechanistic studies of intercalators as allosteric effectors of DNA conformation will continue, emphasizing kinetic studies of the effect of intercalcators on the B to Z transition in DNA. The fundamental thermodynamics and kinetics of the interaction of a series of novel anthrapyrazole antibiotics with DNA will be examined. The combined results of these studies will provide fundamental details essential for understanding the intercalation process, an important reaction by which many clinically useful antibiotics interact with their prime cellular target, DNA.