Date of Award

5-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Legacy Department

Chemistry

Committee Member

Dr. Daniel Whitehead, Committee Chair

Committee Member

Dr. James Morris

Committee Member

Dr. Modi Wetzler

Committee Member

Dr. Andrew Tennyson

Abstract

Human African trypanosomiasis (HAT), commonly called African sleeping sickness, is caused by bloodstream form Trypanosoma brucei and has the potential to affect millions of people in sub-Saharan Africa. Treatments have existed for the past fifty years, but are characterized by severe adverse side-effects and poor efficacy. Trypanosomes generate ATP through glycolysis, or the metabolism of glucose, which is catalyzed by enzymes called hexokinases (TbHK1 and TbHK2) in trypanosomes. Through high-throughput screenings (HTS) and structure-activity relationships (SAR), both hexokinases could be targeted with small molecules to inhibit the first step in the glycolytic pathway of trypanosomes. Of the two hexokinases, TbHK1 has shown promise as a target for the development of trypanocides.

The first half of this thesis will report the syntheses of several derivatives of potent TbHK1 inhibitors, ebselen and benzamidobenzoic acid (BABA). Ebselen, or 2-phenyl-1,2-benzisoselenazol-3(2H)-one, is a drug that is currently in trials for patients suffering from hearing loss or bipolar disorder that has also demonstrated potency against trypanosomes with an IC50 of 0.05 ± 0.03 µM. BABA is a novel therapeutic derivative that was revealed to be a hit through SAR efforts. The final aim is the coupling of the inhibitors to a peptidic scaffold via solid phase peptide synthesis (SPPS). The results of the bioassays conducted on these conjugates will be described and presented with future directions to expand the role of these inhibitors toward other tropical diseases.

The Diels-Alder reaction is a carbon-carbon bond forming reaction in which a dienophile (e.g., alkene or alkyne) and a diene undergo a [4+2] cycloaddition to produce cyclohexene adducts with predictable regiochemistry. The aim of this work is to employ chiral boronate esters that have absolute stereocenters to propagate chiral information in intramolecular Diels-Alder (IMDA) reactions to establish new absolute stereocenters, while retaining the absolute stereocenters originally present on the original chiral boronate esters. The second half of this thesis will present the synthesis of a novel boronate ester possessing both diene and dienophile components to participate in an IMDA cycloaddition, concluding with future research suggestions.

Included in

Chemistry Commons

Share

COinS