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学功能。作为人类疾病的生物标志物，他们的研究对于改善人类健康和确定治疗药物开发的靶点具有重要意义。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。后者是由一种史无前例的酶交叉途径(5-LOX和COX-2)产生的，并已被证明通过一种未知的机制利用小鼠内皮细胞诱导细胞增殖。异呋喃是由非酶自氧化产生的，与帕金森氏病和肺动脉高压(PAH)疾病的发病有关。限制了他们的进一步研究，半缩酮和异呋喃都不容易获得，需要它们的全合成来为进一步的生物学研究提供材料。因此，这项提议的两个主要目标是开发有效的合成路线 半缩酮和异呋喃的数量。所描述的合成方案还允许获得同位素标记的衍生物，以作为量化临床患者细胞和人体体液样本中这些代谢物的内部标准。其他衍生物将作为化学蛋白质组学研究的探针，旨在识别可能与其生物效应相关的细胞靶标。合成异氟醚还将支持旨在验证导致肺动脉高压表型的假想GPCR靶点的研究。总之，这些新的花生四烯酸代谢物的化学合成将使生物医学和临床科学家能够研究它们，目的是改善人类健康。

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.