Metabolites of arachidonic acid and other polyunsaturated fatty acids (PUFAs) comprise a 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 is the overall objective of this proposal to (a) develop new chemical, biochemical, and pharmacological tools; and (b) exploit these tools to elucidate the biogenesis, structure/stereochemistry, physiologic role(s), regulation, and mechanism/site of action of these novel eicosanoids. Specifically, three key areas will be systematically investigated over the next 5-year budget period: (1) The development of efficient, stereospecific synthetic methodology and/or strategies and their application in unambiguous, total syntheses of physiologically relevant metabolites of arachidonic, linoleic, linolenic, and other PUFAs. Chemical standards will be used to confirm structural/stereochemical assignments of new metabolites. (2) Biochemical/Pharmacological studies to (i) ascertain structure activity relationships (SARs) of bioactive metabolites; (ii) prepare and evaluate more stable eicosanoid analogs with agonist or antagonist activity; and (iii) identify, characterize, and isolate putative eicosanoid receptors and other regulatory macromolecules. (3) Develop isozyme-specific P450 inhibitors using (i) structure based rational design; (ii) computational/molecular modeling; and (iii) library screening.
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