DEVELOPMENT OF POLYAMINE ANALOGS AS ANTICANCER AGENTS

拟议工作的目标是研究 多胺表面正电荷对相互作用的分布 与核酸并使用这些结果来设计和合成 具有改变的电荷分布的聚胺类似物可能具有不同的 对核酸的亲和力高于天然存在的多胺。 的 类似物应在物理上取代天然多胺，而不会重复 至少是它们的一些生物学功能。 具体目标是：1） 测量天然存在的多胺的缔合常数和 使用光谱法与 DNA 和多核苷酸合成多胺类似物 方法； 2) 确定多胺类似物是否会模仿 DNA 的缩合和/或 B 到 Z 转变的诱导 由天然存在的多胺引起的特定多核苷酸； 3）到 测试特定类似物对培养物生长和活力的影响 人类和啮齿动物脑肿瘤细胞； 4）研究影响 CENUs 和 Cis-Pt 的细胞毒性是由天然的替代物引起的 与先前鉴定的有效类似物一起出现的多胺：以及，5) 协助类似物对 CENU 和顺式引起的 DNA 交联的影响 铂。 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，目标 3-5 的结果将允许评估 类似物对活细胞的影响可能导致设计 治疗上重要的抗癌剂。

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.