Document Type

Thesis

Date of Degree Completion

Spring 2015

Degree Name

Master of Science (MS)

Department

Chemistry

Committee Chair

Stephen Chamberland

Second Committee Member

Gil Belofsky

Third Committee Member

Levente Fabry-Asztalos

Abstract

Cardiovascular disease has quickly become a major health concern in the United States, with numerous citizens dying from cardiovascular disease each year. Older medications, while effective against cardiovascular disease, are problematic to prescribe. A recently isolated natural product, clavatadine A, selectively inhibits human blood coagulation factor XIa. As a result, the synthesis and biological testing of clavatadine A and synthetic clavatadine A analogues that selectively inhibit factor XIa would represent a new direction in cardiovascular disease research. A potent and selective factor XIa inhibitor has the potential to be a safer replacement for current anticoagulants, such as Warfarin, Pradaxa®, Eliquis®, and Xarelto®. The first total synthesis of clavatadine A was recently completed. Clavatadine A binds irreversibly to the active site of factor XIa; therefore, a primary goal of this research is to design an analogue of clavatadine A that is a selective, reversible factor XIa inhibitor. The general approach developed for the synthesis of guanidine containing natural products was used to attempt to prepare several synthetic analogues of clavatadine A. First, the original four analogues of clavatadine A that included a urea, reverse carbamate and two amide analogues were attempted in hopes to synthesize an analogue that was less likely to form a covalent bond with Ser-195 in the active site of factor XIa. Phase two analogues were also attempted when the orginal four analogues did not work out as planned. Phase two included attempting to make a five carbon clavatadine A.

Language

English

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