Date of Award

5-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical and Chemical Engineering and Sciences

First Advisor

Joshua Rokach

Second Advisor

Nasri Nesnas

Third Advisor

Yi Liao

Fourth Advisor

Maria Pozo de Fernandez

Abstract

1) 5-Oxo-ETE (7, Scheme 1) is the most potent eosinophil chemoattractant among all lipid mediators and it can also stimulate a late-phase asthma attack. It is formed by the biotransformation of arachidonic acid (AA, 1, Figure 1). 5-Oxo-ETE (7) elicits eosinophil migration both in vitro and in vivo when injected intradermally in humans, acting via the highly selective OXE receptor (OXE-R). Our group postulated that a selective OXE-R antagonist might be a useful therapeutic agent in late phase asthma. As a result, the first and only series of OXE receptor antagonists which are structural mimics of 5-oxo-ETE (7) have been designed and synthesized, and the potency of the lead antagonist is as low as 10 nanomolar (S230, 25; S264, 27). Then we developed and studied the 2nd generation antagonists (S025, 67; S48, 68) which block ω-oxidation by replacing the methyl group on the ω-end of the molecule with the phenyl group; during the biostudy, each of the alkyl phenylindoles forms a single major metabolite by a novel α-indole hydroxylation pathway. These more polar metabolites may have a lower plasma protein binding property and become a new series of antagonists themselves. 2) Alzheimer’s disease (AD) is a progressive neuro-degeneration of the brain; this irreversible progress is caused by the loss of neurons and relates to the oxidative stress in the brain. Current methods for the detection of Alzheimer’s disease (AD) are based on clinical observations that lack molecular standards. Due to the preponderance of docosahexaenoic acid (DHA, 3, Figure 1) in brain tissue, the level of neuroprostanes can be used as an index of free-radical lipid peroxidation and as a biomarker of oxidative stress which can help in the detection and diagnosis of the development of Alzheimer’s disease. This dissertation describes two novel strategies for the synthesis of neuroprostane intermediates.

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