DEVELOPMENT OF POLYAMINE ANALOGS AS ANTICANCER AGENTS

拟议工作的目标是研究 多胺表面正电荷在相互作用中的分布 并利用这些结果来设计和合成 具有修饰的电荷分布的多胺类似物，其可能具有不同的 与自然产生的多胺相比，核酸的亲和力更强。这个 类似物应在物理上取代天然多胺，而不是在 至少它们的一些生物学功能。具体目标是：1) 测量自然产生的多胺的缔合常数和 DNA和多核苷酸合成多胺类似物的光谱研究 方法；2)确定多胺类似物是否会模仿 DNA的缩合和/或诱导B到Z的转变 由天然多胺引起的特定多核苷酸；3)至 检测特定类似物对培养物生长和活力的影响 人和啮齿动物脑瘤细胞；4)研究其对小鼠脑肿瘤细胞生长的影响 天然-cenus和顺铂的细胞毒作用 已确定有效类似物存在的多胺：和，5) 为了辅助类似物对CENU和cis引起的DNA交联的影响- PT.在目标1和目标2中获得的结果将用于选择和设计 有效的类比，AIMS 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 具有重要治疗意义的抗癌药物。

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.