Date of Award

12-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical and Chemical Engineering and Sciences

First Advisor

Joshua Rokach

Second Advisor

Alan Brown

Third Advisor

Norito Takenaka

Fourth Advisor

Andrew Palmer

Abstract

Arachidonic acid (AA, 4, Figure 1) is a 20:4 (ω-6) fatty acid with a 20-carbon chain and four cis-double bonds, and the esterified form of AA in phospholipids can be enzymatically liberated by phospholipases (PL) and subsequently metabolized into a variety of physiologically important mediators known as eicosanoids (Figure 2). One of the most important eicosanoids is 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE, 17). The 5-oxo-ETE (17) is the most known potent chemotactic factors for human eosinophils, and it can stimulate the late-phase asthma attacks.¹ To determine how the biosynthesis of 5-oxo-ETE is regulated, so as to determine its pathophysiological roles in the late-phase asthma attack, we designed and synthesized affinity chromatography ligands for the purification of 5-HEDH (Figure 2). Also, because of the potent activity of 5-oxo-ETE, we designed and synthesized a series of 5-oxo-ETE receptor antagonists for the asthmatic disease (Figure 2). This dissertation describes the studies I have accomplished. In addition to the enzymatic pathways, radical reactions are another important transformation pathways of AA (4, Scheme 1). The reaction between reactive oxygen species (ROS) and AA produces isoprotanes (iPF₂ₐ, 21, 25, 29, and 33, Scheme 1), which are important biomarkers of the severity of oxidative stress.² It is now widely accepted that the iPF₂ₐ could be a specific, sensitive, and selective biomarker for measuring the severity of AD.²ᵃ, ²ᶜ, ²ᵈ, ³. This dissertation describes a novel strategy for the synthesis of iPF₂ₐ, which allows the development of a reliable diagnostic assay for AD.

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