Terrab, Leila
(2021)
Small Molecule Inhibitors of the Artemis Endonuclease and
Thiadiazines as HSP70 Agonists.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The first chapter of this dissertation covers the analog synthesis of three screening hit compounds previously identified as Artemis inhibitors. Artemis is a metalloenzyme nuclease involved in the nonhomologous end-joining pathway, a DNA damage repair pathway. The screening hits included the hydroxamic-acid containing Droxinostat, a 2-amino-3-carboxythiophene, and a 2-aminothiazole. Previous work by our group identified chromane analogs of Droxinostat to show Artemis inhibition, and this work mostly focuses on exploring new substitution patterns of the chromane scaffold for our structure-activity relationship (SAR) studies. While a few of the chromane analogs inhibited Artemis, they have also been shown to target histone deacetylases (HDACs), another family of metalloenzymes. None of the 2-amino-3-carboxythiophene nor 2-aminothiazole analogs have shown Artemis inhibition. The Artemis crystal structure has only become available in February 2020, and our group used an Artemis homology model and SAR studies to guide our compound design.
The second chapter covers the selective functionalization of the 1,2,6-thiadiazine 1,1-dioxide scaffold for the synthesis of medicinally relevant compounds. We employed chemoselective transformations of the thiadiazine’s sulfamide nitrogens and vinylogous carbamate. We were interested in using the sulfamide group as a bioisosteric replacement to the urea substructure of MAL1-271, an HSP70 agonist. HSP70 proteins are ATP-dependent molecular chaperones that regulate protein folding, and HSP70 modulation has shown a therapeutic potential in neurodegenerative diseases, such as Huntington’s Disease. Our collaborators evaluated our compounds in a Huntington Disease model, where their ability to reduce polyglutamine (polyQ) aggregates was assayed. A few analogs have shown higher efficacy than MAL1-271. We also decided to utilize our method for the synthesis of thiadiazine-containing HDAC6 inhibitors; however, our assays did not show a promising HDAC inhibition profile.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
3 May 2021 |
| Date Type: |
Publication |
| Defense Date: |
11 December 2020 |
| Approval Date: |
3 May 2021 |
| Submission Date: |
3 February 2021 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
274 |
| 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: |
Artemis Endonuclease
HSP70
Thiadiazines |
| Date Deposited: |
03 May 2022 05:00 |
| Last Modified: |
19 May 2023 14:04 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/40218 |
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