Synthesis of inhibitors targeting the downstream enzymes in the isoprenoid biosynthetic pathways

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Zhou, Xiang
The University of Iowa; University of Iowa
publicabstract; Chemistry
thesis / dissertation description
The nitrogenous bisphosphonates pamidronate, alendronate, risedronate, and zoledronate are used clinically in the treatment of bone disease. All of these drugs inhibit the enzyme farnesyl diphosphate synthase (FDPS), which mediates production of farnesyl diphosphate (FPP). However, because it is a branch point in isoprenoid biosynthesis, FPP is involved in the biosynthesis of several different substrates at the same time.One key enzyme downstream of FDPS in isoprenoid biosynthesis is geranylgeranyl diphosphate synthase (GGDPS) which affords the geranylgeranyl diphosphate (GGPP) necessary for prenylation of the small GTPases such as Ras, Rab, Rho and Rac, that are important signaling proteins. Non-nitrogenous analogues of the clinical drugs, including mono- and bisisoprenoid bisphosphonates, have been developed more recently. These new analogues have been found to inhibit GGDPS selectively. Because it is important to inhibit the generation of GGPP, selective inhibition of GGDPS is highly desirable. In previous research, digeranyl bisphosphonate (DGBP) was discovered to show good inhibition of GGDPS. In order to obtain more potent analogues of the compound DGBP, and to study the biological effect of an á-alkoxy group on bisphosphonate compounds, a series of ether bisphosphonates has been prepared and studied.A second important enzyme in isoprenoid biosynthesis is geranylgeranyl transferase II (GGTase II). This enzyme transfers GGPP to Rab proteins, and thus converts the parent proteins to lipoproteins which are essential for their proper cellular localization. One known inhibitor of this enzyme is the chemical 3-PEHPC, but a high concentration of this compound is necessary to generate any cellular effects. In an effort to study the cellular effects that result from inhibition of this enzyme, and to develop more potent inhibitors, my research has focused on modification of 3-PEHPC to obtain derivatives that may have improved biological activity. Both the known compounds 3-PEHPC and 3-PEPC, and new structures, including the first generation PEHPC N-oxides and the second-generation compounds prepared through click chemistry, have been prepared and tested for activity in this system.