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体的重要成分，参与多种细胞功能，包括炎症介质和多种稳态生物学功能。它们的研究对于改善人类健康作为人类疾病的生物标志物和鉴定治疗剂开发的靶点是重要的。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，半缩酮和异呋喃。后者是通过前所未有的酶促交换途径（5-LOX和考克斯-2）产生的，并且已经显示通过未鉴定的机制使用小鼠内皮细胞诱导细胞增殖。异呋喃是通过非酶促自氧化产生的，并且与帕金森病和肺动脉高压（PAH）疾病的发病机制相关。限制了它们的进一步研究，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，该提议的两个主要目的是开发有效的合成路线， 半缩酮和异呋喃的量。所描述的合成方案还允许获得同位素标记的衍生物，以用作用于定量临床患者的细胞和人类流体样品中的这些代谢物的内标。其他衍生物将作为化学蛋白质组学研究的探针，旨在鉴定可能与其生物学效应相关的细胞靶点。合成异呋喃也将支持旨在验证导致肺动脉高压表型的假设GPCR靶标的研究。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以改善人类健康为目的对其进行研究。

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.