Arachidonic acid metabolites are important constituents of humans involved in a variety of cellular functions including mediators of inflammation and a variety of homeostatic biological functions. Their study is important for the improvement of human health as biomarkers of human disease and identification of targets for the development of therapeutic agents. Recently, investigators at Vanderbilt University have described two new groups of arachidonic acid metabolites, the hemiketals and isofurans. The latter are produced by an unprecedented enzymatic cross-over pathway (5-LOX and COX-2) and have been shown to induce cell proliferation using mouse endothelial cells by an unidentified mechanism. The isofurans are generated by non- enzymatic autoxidation and have been associated with the pathogenesis of Parkinson's disease and pulmonary arterial hypertension (PAH) disease. Limiting their further study, both the hemiketals and isofurans are not readily available requiring their total synthesis to provide material for further biological investigations. Thus two primary aims of this proposal are to develop efficient synthetic routes to the hemiketals and isofurans in quantity. The described synthetic schemes also allow access to isotopically labeled derivatives to serve as internal standards for the quantification of these metabolites in cells and human fluid samples of clinical patients. Other derivatives will serve as probes for chemical proteomic studies aimed at the identification of cellular targets possibly relevant to their biological effects. Synthetic isofurans will also support studies aimed at verifyng a hypothetical GPCR target leading to the pulmonary arterial hypertension phenotype. In summary chemical synthesis of these novel arachidonic acid metabolites will enable their study by biomedical and clinical scientists with the purpose of improving human health.
Among natural products the study of arachidonic acid metabolites have a long history as important to the improvement of human health including the development of therapeutic agents and diagnosis of human disease. Herein, we propose the total synthesis of two families of novel arachidonic acid metabolites discovered at Vanderbilt University with importance in inflammation and pulmonary arterial hypertension. In collaboration with the labs responsible for the discovery of these metabolites we outline a program enabled by chemical synthesis to advance the further study of these metabolites with possible clinical application.
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