The past decade ha seen a dramatic increase in the number and diversity of metabolites derived from arachidonic acid and its congeners. The list of oxygenated products now includes leukotrienes (LTs). lipoxins, delta- and Tau-ketols, dihydroxyeicosatetraenoic acids (DiHETEs), trioxylins and several related epoxy-alcohols and polyols. More recently, Capdevila and others have elucidated a third branch of the arachidonate cascade mediated by cytochrome P-450. This ubiquitous enzyme system catalyzes three types of primary oxidation reactions: a) olefin epoxygenation (epoxygenase) generating four regioisomeric cis-epoxyeicosatrienoic acids (EETs); b) allylic oxygenation resulting in six regioisomeric hydroxyeicosatetraenoic acids (HETEs) and c) hydroxylation of an sp3 hybridized carbon (monooxygenase). Partly as a consequence of interdisciplinary collaborations between chemists and biomedical researchers, or knowledge of eicosanoid chemistry and pharmacology has progressed rapidly. These achievements are especially noteworthy when one considers that most arachidonate metabolites are available in only minute amounts from natural sources. Confirmation of structure, analytical measurements, and biological evaluations have in many instances relied on the availability of authentic synthetic material and on the development of analogues and/or inhibitors. As part of an integrated investigation into the production, metabolism, regulation, and function of non-cyclooxygenase renal eicosanoids, this project will: (1) Develop synthetic strategies and methodology for producing sufficient quantities of eicosanoids (labeled and unlabeled) for biological evaluation; (2) Synthesize structural variants for structure-activity assessment; (3) Confirm structure and stereochemical assignments of novel eicosanoids by unambiguous total synthesis; and (4) Prepare specific inhibitors and eicosanoid analogues with modified activity or stability.
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