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

Kavoosi, Sam (2022) Development of Small-Molecule and Nucleoside Based Probes Targeting Epigenetic and Metabolic Enzymes. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Kavoosi, Samsak226@pitt.edusak226
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairIslam, Kabirulkai27@pitt.edukai27
Committee MemberSeth, Hornehorne@pitt.eduhorne
Committee MemberPaul, Floreancigflorean@pitt.eduflorean
Committee MemberDas,
Date: 11 October 2022
Date Type: Publication
Defense Date: 22 July 2022
Approval Date: 11 October 2022
Submission Date: 26 July 2022
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 236
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: chemical biology
Date Deposited: 11 Oct 2022 20:40
Last Modified: 11 Oct 2022 20:40


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