DNA TOPOISOMERASE II AS A THERAPEUTIC TARGET

描述：拟议研究的目的是发现和发展 作为潜在的DNA拓扑异构酶II的独特的非插层抑制剂 抗肿瘤药物。人工合成拓扑异构酶II类药物的研究进展 导致了一个模型药效团，它吸收了 许多插层型和非插层型试剂。基于这些 通过研究，设计了蓝藻毒素的原型剂。阿扎毒素是一种强效的 拓扑异构酶II结合的DNA链断裂的诱导物。的研究 印加毒素及其相关化合物的构效关系 因为对其他人发表的工作的考虑有助于改进该模型。 具体目标是合成独特的结构类 拓扑异构酶II导向的药物，(1)结合 Anthracycline-epipodophyllotoxin/azatoxin/qunotoxin核(2)具有 他们的模型中提出的DNA插层-小槽结合基序和(3) 有可能经历重大的结构性变化的 生物还原或谷胱甘肽结合和/或低氧条件(4) 它们是非嵌入性的，并且有可能被光激活 在与可切割的络合物结合时与DNA交联；以及(5) 在次要凹槽之间具有定义的构象关系 在他们的模型中结合和DNA插层结构域。最后，在一个 试图为拓扑异构酶II的作用机制提供新的信息 有毒的细胞毒性，他们会比较阿尔法和贝塔的敏感性 拓扑异构酶II同工酶对不同类似物，定量水平的影响 单链和双链DNA断裂，并可能通过合作， 药物诱导的RAS体外切割活性的强度 原癌基因。

DESCRIPTION: The aim of the proposed research is to discover and develop unique, non-intercalative inhibitors of DNA topoisomerase II as potential antineoplastic agents. Prior studies on synthetic topoisomerase II agents led to a model pharmacophore that assimilated the structural elements of many intercalative and non-intercalative classes of agents. Based on these studies, the prototype agent azatoxin was designed. Azatoxin is a potent inducer of topoisomerase II -bound DNA strand breaks. Studies of structure-activity relationships of azatoxin and related compounds as well as consideration of work published by others has helped to refine the model. The specific aims are to synthesize unique structural classes of topoisomerase II-directed agents that (1) incorporate the anthracycline-epipodophyllotoxin/azatoxin/qunotoxin nuclei (2) possess the DNA intercalation-minor groove binding motif proposed in their model and (3) that possess the potential to undergo significant structural alteration upon bioreduction or glutathione conjugation and/or by hypoxic conditions (4) that are non-intercalative and have the potential for photoactivated crosslinking to DNA while bound to the cleavable complex and (5) that possess defined conformational relationships between the minor groove binding and DNA intercalation domains in their model. Finally, in an attempt to provide new information on the mechanism of topoisomerase II poison cytotoxicity, they will compare the sensitivity of the alpha and beta isozymes of topoisomerase II to the different analogs, quantitate the levels of single and double strand DNA breaks and possibly through a collaboration, the intensity of drug-induced in vitro cleavage activity in the ras protooncogene.