Arachidonic acid is oxidatively metabolized by three distinct enzymatic pathways: cyclooxygenase; lipoxygenases; and, the most recently discovered, cytochrome P450. The primary metabolites of these pathways are also subject to a further cascade of enzymatic and non-enzymatic transformations resulting in a rich spectrum of biologically active products. Recent studies have implicated the cytochrome P450 branch of the arachidonate cascade in renal function. Also, novel dual pathway metabolites arising from oxidation of arachidonic acid by both cytochrome P450 and cyclooxygenase have been isolated and demonstrated to have potent vasoconstrictor activity in the kidney. The many urgent questions concerning the biogenesis, regulation, and disposition of these eicosanoids in the kidney and their physiological role in renal function will be addressed by: a) Development of synthetic strategies and methodology for producing sufficient quantities of eicosanoids (labeled and unlabeled) for biological evaluation; b) unambiguous total chemical syntheses to confirm structure and stereochemical assignments of novel metabolites; c) assessment of structural variants for structure-activity (SAR) relationships; and d) preparation of selective metabolism inhibitors and eicosanoid analogues with modified activity or stability.
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