Chemistry and Biology of Novel Arachidonic Acid Metabolites

描述（由申请人提供）：花生四烯酸代谢物是人类参与多种细胞功能的重要成分，包括炎症介质和各种体内平衡生物功能。它们的研究对改善人类健康具有重要意义，可以作为人类疾病的生物标志物，并为开发治疗药物确定靶点。最近，范德比尔特大学的研究人员描述了两组新的花生四烯酸代谢物，半酮类和异呋喃类。后者是由前所未有的酶交叉途径（5-LOX和COX-2）产生的，并已被证明通过一种未知的机制诱导小鼠内皮细胞的细胞增殖。异呋喃是由非酶促自氧化产生的，并与帕金森病和肺动脉高压（PAH）疾病的发病机制有关。限制了它们的进一步研究，半酮和异呋喃都不容易获得，需要它们的全合成为进一步的生物学研究提供材料。因此，本提案的两个主要目的是开发有效的合成路线

DESCRIPTION (provided by applicant): 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.