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Document Type

Campus Access

Degree Program

Chemistry

Degree Type

Master of Science (M.S.)

Year Degree Awarded

2011

Month Degree Awarded

September

Keywords

FIH, HIF, Inhibition, Oxygen Sensing

Abstract

The control of oxygen delivery to cells in the body is the result of a small group of primary oxygen sensors, one of the most important of which is the hypoxia-inducible transcription factor-1 (HIF-1). Two alpha-ketoglutarate dependent non-heme iron dioxygenases are responsible for the regulation of HIF-1 through hydroxylation of residues on the HIF-1a subunit. One of these enzymes, known as the factor inhibiting HIF-1 (FIH-1) is responsible for hydroxylating residue Asn803 on HIF-1a, preventing the transcription of hypoxia related genes controlled by HIF-1. It was hypothesized that there would be a difference in inhibition of FIH-1 from the other HIF-1 regulating enzyme, the prolyl hydroxylase domain-2 (PHD2), when testing a series of ten small molecule inhibitors. The ten inhibitors chosen fell into three classes: pyrones, pyridines, and catechols. Of these inhibitors, it was found that catechols produced a significant inhibitory difference between PHD2 and FIH, and may provide useful in further inhibitor design and synthesis work.

First Advisor

Michael J. Knapp

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