RUI: Inhibitors of Polyamine and Histone Acetylases and Deacetylases

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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.