Date Approved

7-12-2013

Date Posted

1-14-2016

Degree Type

Campus Only Thesis

Degree Name

Master of Science (MS)

Department

Chemistry

Committee Member

Cory Emal, PhD, Chair

Committee Member

Harriet Lindsay, PhD

Committee Member

Deborah Heyl-Clegg, PhD

Abstract

Plasminogen activator inhibitor (PAI-1) is a member of the serine protease inhibitor (serpin) family of proteins, which inhibits certain serine proteases, such as tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA), and thus is a primary regulator of fibrinolysis, the process that results in breakdown of blood clots. PAI-1 also exhibits effects on various human ailments including atherosclerosis, stroke and diabetes, with which high levels of PAI-1 have been associated. The goal of this research study is to design novel, potent, and specific small molecule inhibitors of PAI-1. The structural intricacy of the PAI-1 allows for multiple prospective binding sites. This research study explores the synthesis and screening of biological activity of various structural analogues of the lead molecule I-26, which was identified through high-throughput screening. It was hypothesized that the structural alterations of the lead molecule would affect the potency of PAI-1 inhibitor. The design rationale, synthesis and structure-activity relationships of novel small molecule inhibitors of PAI-1 are discussed.

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