DESIGN OF DNA BINDING AGENTS FOR RESISTANT TUMORS

抗肿瘤 DNA 结合剂的设计

基本信息

批准号：
3194201
负责人：
WILLIAM A REMERS
金额：
$ 19.45万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
1990
资助国家：
美国
起止时间：
1990-04-01 至 1993-03-31
项目状态：
已结题

项目摘要

The objective of this research is to discover new compounds active against tumors that are resistant to existing anticancer agents. These new compounds will have polycyclic aromatic nuclei designed for strong intercalative binding with DNA,l and side chains with basic amino groups that can confer water solubility upon salt formation. The amine pKa will be controlled to permit both good DNA binding and cell penetration. Computer modeling and measurement or calculation of physical properties will aid the design of these compounds. They will be synthesized by efficient routes based on established types of carbocyclic or heterocyclic chemistry. New compounds will be screened initially in a panel of human tumor cells using the micro culture tetrazolium assay. Tumor cell lines will include two that show multiple drug resistance and express the P-glycoprotein drug efflux pump. The best compounds will be tested against P388 leukemia and multidrug resistant P388 leukemia in mice. Cardiotoxicity will be evaluated in cultured rat myoctes. DNA alkaline election assays will assess topoisomerase II mediated DNA damage including single and double stranded breaks and DNA-protein cross links. Correlations between cytotoxicity and each specific type of DNA damage will be made. From the information obtained above, a comprehensive data base for SAR using antitumor potency, molecular DNA damage, and cardiotoxicity as descriminates will be constructed. It will provide the basis for the design of subsequent analogues. Furthermore, it might provide a better understanding of some of the factors involved in drug resistance by tumor cells and how they can be overcome.

这项研究的目的是发现活跃的新化合物对现有抗癌药具有抗性的肿瘤。这些新化合物将具有设计用于强的多环芳族核与DNA，L和侧链与碱性氨基的结合这可以在盐形成时赋予水溶性。胺PKA将可以控制以允许良好的DNA结合和细胞穿透。计算机建模和测量或计算物理特性将有助于这些化合物的设计。他们将由基于既定类型的碳环或杂环的有效路线化学。最初将在人类肿瘤细胞中筛选新化合物使用微培养四唑分析。肿瘤细胞系将包括两个显示多种耐药性并表达P-糖蛋白药物外排泵。最好的化合物将针对P388白血病和小鼠的多药耐药性p388白血病。心脏毒性将是在培养的大鼠肌周围评估。 DNA碱性选举将评估拓扑异构酶II介导的DNA损伤，包括单和双滞留的断裂和DNA-蛋白交叉链路。之间的相关性将造成细胞毒性和每种特定类型的DNA损伤。从上面获得的信息中，SAR的全面数据库使用抗肿瘤效力，分子DNA损伤和心脏毒性作为描述将构建。它将为随后的类似物的设计。此外，它可能会提供更好的了解肿瘤耐药性涉及的一些因素细胞以及如何克服它们。