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.
Recommended Citation
Gordhan, Heeren Manoj, "A Targeted Drug Delivery Strategy for Trypanosomiasis Towards a Diastereoselective Boronate Ester Mediated Intramolecular Diels-Alder Cycloaddition" (2017). All Dissertations. 1868.
https://tigerprints.clemson.edu/all_dissertations/1868