THE RATIONAL DESIGN & SYNTHESIS OF ANTHRAMYCIN ANALOGS

本建议的总体目标是合理地综合一个 吡咯并（1，4）苯并二氮杂抗肿瘤剂的设计群体。 基于 主要是根据私家侦探的调查实验室足够 存在关于吡咯并（1，4）苯并二氮杂卓 抗生素，如氨霉素，与DNA反应，使新的DNA反应， 化合物可以被设计成能够响应特定的生物化学/生物学特性， 问题包括：这些抗生素的结构特征是什么？ 负责这些药物的高DNA序列特异性， 可以 具有高DNA序列特异性的药物指导遗传事件， 如逆转录病毒插入癌基因和相反它们的删除？ 是 西比罗霉素和阿司拉霉素的心脏毒性，由于形成 醌亚胺？， 吡咯并（1，4）苯并二氮杂卓类化合物的合成 在这项研究中，作为抗肿瘤药物的治疗潜力有所提高？ 这个项目的成功完成需要一个有问题的综合 吡咯并（1，4）苯并二氮杂环庚三烯核中所含的甲醇胺的化学结构。 根据我们对控制这些因素的了解， 内酰胺氢化物还原形成叔甲醇胺的程度 胺或无环氨基醇，我们建立了仿生合成 这些抗生素及其衍生物在 吡咯并（1，4）苯并二氮杂卓基团。 这个应用程序是一个逻辑扩展 我们的整个研究计划的发展炭疽霉素， 这将导致在分子基础上的重要信息， 这组化合物的抗肿瘤活性以及潜在的 治疗上改进的抗癌剂。

The overall objective of this proposal is to synthesize a rationally designed population of pyrrolo(1,4)benzodiazepine antitumor agents. Based primarily upon investigations in the P.I.'s laboratory sufficient information exists on the manner in which pyrrolo(1,4)benzodiazepine antibiotics, such as anthramycin, react with DNA, so that new DNA reactive compounds can be designed that will answer specific biochemical/biological questions such as: What structural features of these antibiotics are responsible for the high DNA sequence specificity of these drugs?, Can drugs which have high DNA sequence specificity direct genetic events such as retrovirus insertion of oncogenes and conversely their deletion?, Is the cardiotoxicity of sibiromycin and athramycin due to formation of quinone-imines?, Do the synthetic pyrrolo(1,4)benzodiazepines prepared during this study have improved therapeutic potential as antitumor agents? The successful completion of this project requires a problematic synthesis of a carbinolamine contained in a pyrrolo(1,4)benzodiazepine nucleus. Based upon our learned understanding of the factors which control the extent of hydride reduction of a lactam to form the carbinolamine, tertiary amine or acyclic amino alcohol we have established a biomimetic synthesis of these antibiotics and their derivatives in the pyrrolo(1,4)benzodiazepine group. This application is a logical extention of our overall research program on the development of the anthramycins, which will lead to important information on the molecular basis for antitumor activity of this group of compounds as well as potentially therapeutically improved anticancer agents in this series.