BourbonP092012D.pdf (12.4 MB)
Development of potential Niemann-Pick type C therapeutics and the synthesis of caged nicotinamide and cholesterol to gain a better understanding of cholesterol biosynthesis and trafficking
thesis
posted on 2012-09-12, 00:00 authored by Pauline BourbonThis thesis describes our endeavors towards the development of therapeutic agents for Niemann-Pick type C disease (NPC), which is a rare, autosomal recessive lipid storage disorder. This fatal disease mainly affects children and nowadays only supportive treatments exist, although two experimental therapies are currently in initial human clinical trials. In collaboration with the Maxfield laboratory at the Cornell Weill Medical School, potential therapeutic agents were developed. The Maxfield group had developed an automated high-throughput screening procedure that measures the level of cholesterol in cells and organelles and identified pyrrolinones as a class of compounds that reduces the level of cholesterol in the lysosomal storage compartment. Based on these results, analogues of this class of compounds were synthesized. Subsequently, different histone deacetylase inhibitors (HDACi) as potential therapy options were explored. Different classes of selective and non-selective HDACi were synthesized. The most potent compound was LBH-589 with an EC50 of less than 5 nM. The third project was to develop tools to gain a better understanding of cholesterol biosynthesis and trafficking. The rate limiting step of cholesterol biosynthesis is the interconversion of HMG-CoA to mevalonate using the enzyme HMG-CoA reductase and presently there remain a number of questions to be answered about this catalytic reaction. In order to elucidate the mechanism of this reaction by Laue crystallography, model caged coumarin of nicotinamide were synthesized. The best caged nicotinamide had a quantum yield of 0.016. Additionally, it was initially demonstrated that caged coumarin-nicotinamide bearing a simple amide bond could not go under cleavage by photolysis. Also, as a tool to study cholesterol trafficking different caged cholesterol were made. The BHC cholesterol could photolysize at 350 nm with a quantum yied of 0.032.
History
Date Modified
2017-06-05Defense Date
2012-08-08Research Director(s)
Dr. Paul HelquistCommittee Members
Dr. Marvin Miller Dr. Richard Taylor Dr. Shahriar MobasheryDegree
- Doctor of Philosophy
Degree Level
- Doctoral Dissertation
Language
- English
Alternate Identifier
etd-09122012-090327Publisher
University of Notre DameProgram Name
- Chemistry and Biochemistry
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