RUI: Inhibitors of Polyamine and Histone Acetylases and Deacetylases

多胺，如腐胺、亚精胺和 精胺在细胞生长和增殖中起重要作用， 然而，它们在细胞代谢中精确功能是未知的。 在 细胞中，多胺与核酸密切相关 并且已经显示出稳定DNA和染色质结构。 这种性质与组蛋白（一种碱性蛋白质）的性质相似 在所有高等生物的细胞核中都发现了与DNA结合的蛋白质。 两 组蛋白和多胺可以在 细胞核也可以被脱乙酰化。 这些乙酰化 去乙酰化反应被认为是调节 转化为DNA建议的主要目标 研究开发新的多胺选择性抑制剂 以及组蛋白乙酰化和去乙酰化，并利用它们来 阐明这些反应的功能。 这些目标 抑制剂将包括核乙酰转移酶， 组蛋白和多胺，核脱乙酰酶， 组蛋白和多胺的细胞质脱乙酰酶。 将为每种化合物设计和合成特定的化合物， 并在试管中测试这些酶的抑制活性 测定。 由于发现了特异有效的抑制剂， 将在活细胞中测试它们对调节 乙酰化组蛋白和多胺水平。 这些新的抑制剂将作为研究工具， 促进我们对组蛋白功能的理解， 正常细胞过程中的多胺。 的意义 乙酰化和去乙酰化对DNA结构和功能的影响将 也要加强。 最终的兴趣和意义是 乙酰化-去乙酰化在特异性调节中的作用 基因表达。

The polyamines, such as putrescine, spermidine, and spermine play an essential role in cell growth and proliferation, however their precise function in cell metabolism is unknown. In cells, the polyamines are closely associated with nucleic acids and have been shown to stabilize DNA and chromatin structure. This property is similar to that of histones, the basic protein found bound to DNA in the nuclei of all higher organisms. Both the histones and polyamines can undergo enzymatic acetylation in the cell nucleus and can also be deacetylated. These acetylation and deacetylation reactions are thought to regulate the binding of these molecules to DNA. The primary goal of the proposed research is to develop new, selective inhibitors for polyamine and histone acetylation and deacetylation, and utilize them to elucidate the function of these reactions. The target for these inhibitors will include the nuclear acetyltransferases for histones and polyamines, the nuclear deacetylases for the histones and the cytoplasmic deacetylase for the polyamines. Specific compounds will be designed and synthesized for each of these enzymes and tested for inhibitory activity in test tube assays. As specific and effective inhibitors are found, they will be tested in living cells for their effect on modulating the level of acetylated histone and polyamine. These new inhibitors will serve as research tools to advance our understanding of the function of histones and polyamines in normal cell processes. The significance of acetylation and deacetylation on DNA structure and function will also be enhanced. Of ultimate interest and significance is the role of acetlyation-deacetylation on the specific regulation of gene expression.