Development of Small-Molecule and Nucleoside Based Probes Targeting Epigenetic and Metabolic Enzymes

In this work I develop biologically relevant chemical synthetic tools to understand the epigenetic landscape. Chemical modifiers in biological systems induce downstream genomic consequences, and the full scale of these modifications is not fully understood. Methylation pathways of DNA and the corresponding genes involved were perturbed with novel oligonucleotide analogues. Alkylated 5-methylcytosine analogues were used to try and regulate these processes. I then developed and synthesized a novel boron-based nucleoside phosphoramidite as tool for potential covalent capture of DNA based hydrolytic enzymes. Many of these oxidative biological changes involve the substrate 2-ketogluterate, which is a product of the tricarboxylic acid cycle. Isocitrate dehydrogenase (IDH), the enzyme responsible for 2-ketogluterate production, is mutated to generate the oncometabolite 2-hydroxygluterate. In this work, I developed novel inhibitors for specific for IDH mutations, which were coupled with a degrader system and resulted in the degradation of these mutations in a glioma cell line