Thesis Title
Discovery of Ten-Eleven Translocation Enzymes Inhibitors for Enhancement of Long-Term Memory
Department or Program
Biological Chemistry
Abstract
It is known that learning and memory involves epigenetic regulations, which alter gene expressions that are involved in the memory process to modify neural plasticity. Specifically, DNA methylation by enzyme DNA methyltransferase (DNMT) at the CpG sites, a process converting cytosine to 5-methylcytosine (5mC), is essential. However, the ten-eleven translocation (TET) family enzymes indirectly remove this epigenetic mark on cytosine, by converting 5mC to 5-hydroxylcytosine (5hmC). The 5hmC is then recognized by DNA repair system, which restores the original cytosine. Behavioral studies with mice showed that the TET gene knock-out mice exhibited enhanced long-term memory. Here, I took a medical chemistry approach, involving organic synthesis, biochemical testing, and computational analysis, to design, synthesize, and evaluation a small molecule that could serve as inhibitors of the TET enzymes. A library of first-generation molecules was synthesized and tested in the enzyme-linked immunosorbent assay (ELISA). A few of these molecules demonstrated inhibition in the micromolar range, with the best molecule identified as “Bobcat339.” A computational analysis by a software Molecular Operating Environment (MOE) was then performed to illustrate the molecular interactions of “Bobcat339” in the TET protein binding sites. Finally, a second-generation molecule was proposed and synthesized with both conjugating structures of great first-generation molecules, and through analysis of the molecular interactions in MOE. The synthetic pathway of this molecule was tested and improved. Ultimately, producing a successful TET inhibitor could result in wide-ranging therapeutic applications for diseases and disorders associated with epigenetic dysregulation, including disorders of memory function.
Level of Access
Restricted: Embargoed [Bates Community After Expiration]
First Advisor
Kennedy, Andrew
Date of Graduation
5-2019
Degree Name
Bachelor of Science
Recommended Citation
Sun, Haoyu, "Discovery of Ten-Eleven Translocation Enzymes Inhibitors for Enhancement of Long-Term Memory" (2019). Honors Theses. 295.
https://scarab.bates.edu/honorstheses/295
Number of Pages
134