Date Approved

7-14-2016

Degree Type

Open Access Thesis

Degree Name

Master of Science (MS)

Department or School

Chemistry

Committee Member

Cory Emal, PhD, Chair

Committee Member

Gregg Wilmes, PhD

Committee Member

Maria Milletti, PhD

Abstract

Plasminogen activator inhibitor type-1 (PAI-1) is a member of the serine protease inhibitor (serpin) family. PAI-1 is involved in the regulation of fibrinolysis, which is the breakdown of blood clots. PAI-1 inhibits serine proteases tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA), which are key factors in fibrinolysis. Excess levels of PAI-1 have also been shown to increase the risk of diabetes, stroke, and atherosclerosis, as well as tumor development. Previous attempts at synthesizing a practical drug for the regulation of PAI-1 have not been successful; therefore, it has been the purpose of this study to further advance progress in this area. Working from a lead molecule derived from a high-throughput library screen, different derivatives were synthesized and tested for anti-PAI-1 activity. By studying the relationships between different aromatic substitutions, our goal was to discover a connection between these substitutions and more potent inhibition of PAI-1. This study discusses the synthesis and impact of the different derivatives of those small molecules on PAI-1 inhibition.

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