| Arachidonic acid (AA) is converted to various biologically active metabolites by different pathways, the most important of which are initiated by 5-lipoxygenase (5-LO) and cyclooxygenase (COX). 5-LO oxidizes AA to 5-HpETE (5-hydroperoxy-6,8,11,14-eicosatetraenoic acid), which is either converted to the corresponding 5-hydroxy compound 5-HETE or to leukotrienes. 5-HETE, although possessing only weak biological activity itself, is oxidized to 5-oxo-ETE, a potent proinflammatory mediator. The actions of these 5-LO products are principally mediated by four highly selective receptors. We previously discovered the pathway leading to the formation of 5-oxo-ETE and showed that this substance is a potent chemoattractant for eosinophils and neutrophils. Although the 5-oxo-ETE receptor (i.e. the OXE receptor) was recently cloned, the physiological role of 5-oxo-ETE is not well understood, and the enzyme responsible for its formation (5-HEDH, 5-hydroxyeicosanoid dehydrogenase) has not yet been fully characterized or cloned. 5-HEDH is present in most types of inflammatory cells. Oxidation of 5-HETE to 5-oxo-ETE by this enzyme is limited by the availability of NADP+, which is normally present at very low concentrations in cells unless they are subjected to oxidative stress.;Our main goal was to determine how the biosynthesis of 5-oxo-ETE is regulated and to determine its pathophysiological roles. To achieve this task we designed and synthesized affinity chromatography ligands for the purification of the enzyme. Also, we designed and synthesized a series of 5-oxo-6E,8 Z-dienoic acids to study the requirements for the activation of 5-oxo-ETE receptor. This information will be helpful for the design and synthesis of inhibitors and agonists for this enzyme, as well as to synthesize 5-oxo-ETE receptor antagonist.*;Isoprostanes (iP) are products of free-radical peroxidation of arachidonic acid 5 (AA) and other polyunsaturated fatty acids (PUFA) such as arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). We have shown that the measurement of iPs in urine can be used as an index of the severity of inflammatory diseases such as Alzheimer's (AD) and atherosclerosis. We have proposed two mechanisms for the formation of iPs and have also proposed an in-depth nomenclature system for naming the isoprostanes.*;We wanted to develop a more efficient and general approaches to iPs and their intermediates, in particular to all-syn iPs. A new and stereoselective approach for the synthesis of all-syn iPs was established. This method is based on hydroboration using catechol borane and Wilkinson's catalyst. To demonstrate the usefulness of this approach, the first total synthesis of all-syn iP, 8,12-iso -iPE2alpha-III 187 was accomplished. Furthermore, this method can also be useful in the synthesis of another all-syn iP, 8,12- iso-iPD2alpha-III 188.;*Please refer to dissertation for diagrams. |
