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 具有改变的电荷分布的多胺类似物， 与天然存在的多胺相比，对核酸的亲和力更高。 的 类似物应该在物理上取代天然多胺，而不重复， 至少有一些生物学功能。 具体目标是：1） 测量天然存在的多胺的缔合常数， 使用光谱法用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拟 DNA的缩合和/或DNA的B到Z转变的诱导。 由天然存在的多胺引起的特异性多核苷酸; 3） 测试特定类似物对培养的细胞的生长和活力的影响， 人和啮齿类动物脑肿瘤细胞; 4）研究对 CENUs和顺式铂的细胞毒性由天然- 与先前鉴定的有效类似物一起存在的多胺;和，5） 以辅助类似物对由CENU和顺式- 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 类似物对活细胞的影响，这可能导致设计 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.