Metabolites of arachidonic acid (AA) and other polyunsaturated fatty acids (PUFAs) comprise a large and structurally diverse family of endogenous autacoids, second messengers, and regulators that maintain homeostasis, modulate physiologic responses, and contribute to pathologic conditions. Known collectively as eicosanoids, the primary metabolites are subject to a further cascade of enzymatic and non- enzymatic transformations resulting in a host of secondary metabolites that together constitute the """"""""arachidonate cascade"""""""". Recent studies from this and other laboratories have revealed a variety of new, bioactive additions to the cascade, especially from the recently discovered cytochrome P450 branch. It has been the long-term objective of this laboratory to (a) develop new chemical, biochemical, and pharmacological tools;and (b) to exploit these tools to elucidate the biogenesis, structure/stereochemistry, physiologic role(s), regulation, site of action and mechanism of these novel eicosanoids. During the next budget cycle, these long-term objectives will be broadly pursued, but three key areas will be emphasized and systematically investigated: 1. Synthetic Methodology/Total Syntheses (a) Asymmetric synthesis of 1-hydroxystannanes (b) Cross-coupling of protected 1-hydroxystannanes with sp2-halides (c) Ir-catalyzed C-H functionalization of olefins (d) Selective ester reductions using manganese catalysts (e) Asymmetric Payne epoxidation: Stereocontrolled synthesis of hydroxylated EETs 2. PUFA Metabolite Agonists and Antagonists (a) Prepare PUFA metabolite analogs with agonist or antagonist activity (b) Optimize and evaluate analogs for in vitro and in vivo activity in collaborative pharmacological/physiological studies 3. Characterization, Isolation and Identification of CYP PUFA Metabolite Receptors and Other Regulatory Macromolecules (a) EET receptor (b) 17,18-Epoxy-EPA receptor (c) 20-HETE receptor
polyunsaturated fatty acids are obtained from our diets and transformed into a large family of metabolites that help maintain homeostasis, modulate physiologic responses, and contribute to pathologic conditions. It is the long-term objective of this laboratory to identify these metabolites, develop biochemical and chemical tools to better understand their physiologic roles, and ultimately intervene pharmacologically.
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