INTERACTIONS OF ANTITUMOR AGENTS WITH NUCLEIC ACIDS

抗肿瘤剂与核酸的相互作用

• 批准号: 2090463
• 负责人: David E Graves
• 金额: $ 9.67万
• 依托单位: UNIVERSITY OF MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-03-01 至 1996-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2090463
• 关键词: DNA; DNA topoisomerases; adduct; affinity labeling; aminoacridines; analog; antineoplastics; biophysics; chemical binding; chemical kinetics; chemical models; chemical structure function; chemical substitution; conformation; drug interactions; enzyme complex; enzyme inhibitors; fluorescence spectrometry; hydrogen bond; methane sulfonate; nuclear magnetic resonance spectroscopy; nucleic acid sequence; nucleic acid structure; pharmacokinetics; photolysis; synthetic nucleic acid; thermodynamics

This project will explore the biophysical properties associated with the interactions of selected antitumor agents (and their structurally relevant analogs) with nucleic acids. During the course of this research, efforts will be focused towards correlating the physical- chemical nature of these drug-DNA interactions with their biological effectiveness as topoisomerase II inhibitors. Experiments will be designed to address questions concerning the physical and/or chemical properties which dictate topoisomerase II inhibition, whether these properties are related to the DNA binding of these compounds, and finally, the mechanism(s) by which they elicit topoisomerase II inhibition. The proposed mechanism by which several of the leading antitumor agents, including m-AMSA, VP-16, VM-26, adriamycin, daunorubicin, and mitoxantrone mediate antitumor activity is through the inhibition of topoisomerase II activity. Information concerning the actual mechanism by which the drugs exert this type of inhibition effect is limited. However, the ability for these compounds to interact with DNA does appear to be an essential requirement for inhibition of the topoisomerase II to occur. We have designed, synthesized, and characterized a series of anilinoacridine compounds with modifications to both the N-phenyl side chain and to the acridine ring to use as probes for examining the structural requirements necessary for drug- induced topoisomerase II inhibition to occur. This series of acridine analogs provide a unique opportunity for examining and characterizing both the physical-chemical properties associated with ternary complex formation and evaluating the influence of chemical substituent type and position on mediating topoisomerase II activity. The activities of these compounds is presumed to reside in formation of a ternary complex between the topoisomerase II-DNA and drug. We will probe the structural and functional properties of this ternary complex, using a variety of methods including photoaffinity crosslinking of the antitumor agent to the DNA (and/or topoisomerase II). The 3-azido-m-AMSA will provide an ideal probe for examining the topoisomerase-DNA-drug ternary complex and provide insight into the mechanism(s) by which m-AMSA exerts its biological effects. Prior to photolysis, this compound has been demonstrated to bind DNA in a manner identical to the parent m-AMSA. Upon photolysis, the azido is converted to the reactive nitrene which forms a covalent attachment in situ. Our laboratory has recently observed that the noncovalent addition of 3-azido-m-AMSA was just as effective in eliciting topoisomerase II inhibition as the parent m- AMSA; indicative of its effectiveness as a probe for examining the mechanistic properties of m-AMSA. With this probe, we will attempt to obtain insight into the overall geometry of the ternary complex (i.e., the location of drug with respect to topoisomerase II and DNA). In addition, our studies will examine the binding properties and topological specificities associated with topoisomerase II-DNA interactions in the absence and presence of topoisomerase II inhibiting antibiotics. These studies on several selected antitumor agents (analogs) will provide insight into our overall understanding of how these compounds exert their potent biological effects and the nature of the drug-DNA complexes, thus leading to a more rational design of novel antitumor agents.

该项目将探索与生物物理特性相关的 选定的抗肿瘤药物(及其结构)的相互作用 相关的类似物)与核酸。在这个过程中 研究，努力将物理- 这些药物的化学性质-DNA与其生物相互作用 作为拓扑异构酶II抑制剂的有效性。实验将是 旨在解决有关物理和/或化学物质的问题 决定拓扑异构酶II抑制的性质，无论这些 性质与这些化合物的DNA结合有关，并且 最后，它们诱导拓扑异构酶II的机制(S) 抑制力。 建议的机制是几种领先的抗肿瘤药物 药物包括m-AMSA、VP-16、VM-26、阿霉素、柔红霉素和 米托蒽醌介导的抗肿瘤活性是通过抑制 拓扑异构酶II活性。关于实际机制的信息 药物发挥这种抑制作用的作用是有限的。 然而，这些化合物与DNA相互作用的能力 似乎是抑制大脑功能的基本要求 拓扑异构酶II发生。我们设计、合成和 表征了一系列具有修饰作用的苯胺吖啶类化合物 N-苯基侧链和吖啶环都用作 关于审查药品所需结构要求的探讨 诱导拓扑异构酶II抑制。本系列吖啶类药物 类比为检验和表征提供了一个独特的机会 三元络合物的物理化学性质 化学取代基类型及影响因素的形成与评价 关于调节拓扑异构酶II活性的立场。的活动 这些化合物被认为以三元络合物的形式存在。 拓扑异构酶II-DNA与药物之间的关系。我们将探索结构上的 和功能性质的这种三元络合物，使用各种 方法包括抗癌剂的光亲和交联法 DNA(和/或拓扑异构酶II)。3-叠氮-m-AMSA将提供一种 检测拓扑异构酶-DNA-药物三元复合体的理想探针 并洞察了m-amsa发挥其作用的机制(S)。 生物效应。在光解之前，这种化合物已经 证明以与亲本m-AMSA相同的方式结合DNA。 在光解过程中，叠氮被转化为反应性的氮 在原位形成共价连接。我们的实验室最近进行了 观察到3-叠氮基-m-AMSA的非共价加成与 有效地诱导拓扑异构酶II抑制作为亲本m- AMSA；表明其作为检查 M-AMSA的力学性能。通过这个探测器，我们将尝试 获得对三元络合物的整体几何结构的洞察(即， 药物相对于拓扑异构酶II和DNA的位置)。在……里面 此外，我们的研究将检查绑定属性和 拓扑异构酶II-DNA的拓扑特异性 拓扑异构酶II抑制的存在和缺失的相互作用 抗生素。 这些对几种选定的抗肿瘤药物(类似物)的研究将 让我们深入了解这些化合物是如何 发挥其强大的生物效应和药物的性质--DNA 络合物，从而导致更合理的新型抗肿瘤设计 探员们。