THE RATIONAL DESIGN & SYNTHESIS OF ANTHRAMYCIN ANALOGS

合理的设计

• 批准号: 3172895
• 负责人: LAURENCE H. HURLEY
• 金额: $ 6.51万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-08-01 至 1986-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3172895
• 关键词: aminoalcohol; antineoplastic antibiotics; benzodiazepines; drug adverse effect; drug design /synthesis /production; drug metabolism; imines; lactams; neoplasm /cancer pharmacology; nucleic acid structure; pyrroles; quinones; tertiary amine

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.

该提案的总体目标是综合合理的 吡咯并(1,4)苯二氮卓类抗肿瘤药物的设计群体。 基于 主要基于 P.I. 实验室的充分调查 存在关于吡咯并(1,4)苯二氮卓类药物的方式的信息 抗生素，如蒽霉素，会与 DNA 发生反应，从而产生新的 DNA 反应 可以设计能够回答特定生化/生物问题的化合物 诸如以下问题：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 序列特异性的药物直接遗传事件，例如 作为逆转录病毒插入癌基因和相反地删除它们？, 是 西伯霉素和阿霉素的心脏毒性是由于形成 醌亚胺？, 合成吡咯并(1,4)苯二氮卓类药物是否可以制备 在这项研究期间是否提高了作为抗肿瘤药物的治疗潜力？ 该项目的成功完成需要有问题的综合 吡咯并(1,4)苯二氮卓核中含有的甲醇胺。 基于我们对控制因素的了解 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已经建立了仿生合成 这些抗生素及其衍生物 吡咯并(1,4)苯二氮卓类。 该应用程序是一个逻辑扩展 我们关于蒽霉素开发的总体研究计划， 这将带来有关分子基础的重要信息 这组化合物的抗肿瘤活性以及潜在的 该系列中治疗效果得到改善的抗癌药物。