DEVELOPMENT OF POLYAMINE ANALOGS AS ANTICANCER AGENTS

作为抗癌剂的聚胺类似物的开发

• 批准号: 3459329
• 负责人: Hirak S. Basu
• 金额: $ 7.81万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-01-01 至 1994-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3459329
• 关键词: DNA; Rodentias; antineoplastics; brain neoplasms; cis platinum compound; crosslink; drug design /synthesis /production; electron density; human tissue; intermolecular interaction; neoplastic cell; nucleic acids; polyamines; polynucleotides; spectrometry; tissue /cell culture

The objectives of the proposed work are to study the effect of the distribution of surface positive charges of polyamines on the interactions with nucleic acids and to use these results to design and synthesize polyamine analogs with modified charge distributions that may have different affinities for nucleic acids than the naturally-occurring polyamines. The analogs should physically replace natural polyamines without duplicating at least some of their biological functions. The specific aims are: 1) to measure the association constants of naturally-occurring polyamines and synthetic polyamine analogs with DNA and polynucleotides using Spectroscopic methods; 2) to determine whether polyamine analogs will mimic the condensation of DNA and/or the induction of the B to Z transition of specific polynucleotides caused by naturally-occurring polyamines; 3) to test the effects of specific analogs on the growth and viability of cultured human and rodent brain tumor cells; 4) to study the effects on the cytotoxicity of CENUs and Cis-Pt caused by replacement of naturally- occurring polyamines with effective analogs previously identified: and, 5) to assist the effects of analogs on DNA crosslinking caused by CENU and cis- Pt. Results obtained in Aims 1 and 2 will be used to choose and design effective analogs, and results from Aims 3-5 will allow evaluation of the effects of analogs on living cells that may lead to the design of therapeutically important anticancer agents.

拟议工作的目标是研究 多胺在相互作用上的表面正电荷分布 与核酸一起使用这些结果来设计和合成 带有修改的电荷分布的多胺类似物可能具有不同 核酸的亲和力比自然呈现的多胺。 这 类似物应物理替代天然多胺而不重复 他们的生物学功能至少。 具体目的是：1） 测量天然多胺的关联常数和 使用光谱学的合成多胺类似物与DNA和多核苷酸类似物 方法; 2）确定多胺类似物是否会模仿 DNA的凝结和/或B的诱导B到Z转变的诱导 由天然多胺引起的特异性多核苷酸； 3）到 测试特定类似物对培养的生长和生存能力的影响 人和啮齿动物脑肿瘤细胞； 4）研究对 Cenus和CIS-PT的细胞毒性是由自然替代而引起的 以前鉴定出有效类似物的多胺发生：和，5） 有助于类似物对CENU和顺式引起的DNA交联的影响 pt。 目标1和2中获得的结果将用于选择和设计 有效的类似物以及目标3-5的结果将允许评估 模拟对活细胞的影响可能导致设计 在治疗上重要的抗癌药。