Pohorilets, Ivanna
(2022)
Kinetic Study and Development of Ligand-Accelerated Clip Reactions and Synthesis of a Tetrahydrofuran Analog of FR901464.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
This is the latest version of this item.
Abstract
Fluorescence has found many uses in the areas of analytical, organic, biological, and physical chemistry. Herein, fluorescence was used to study the kinetics of Tsuji-Trost reaction under biologically relevant conditions. The Tsuji-Trost reaction was studied using a fluorogenic substrate, which allowed for high throughput, accurate data collection and revealed three kinetic regimes. The turnover limiting step was found to depend on the substrate concentration and reaction temperature.
Florescence was also used to develop and optimize palladium-catalyzed clip reaction. Currently, deallylation is deemed to be too slow to be viable uncaging reaction and more rapid, palladium-catalyzed propargylic C-O or C-N bond cleavage is typically used. These studies avoid using phosphine ligands, known to accelerate the reaction. Here, new phosphine ligands were synthesized and tested under biological conditions. This palladium-catalyzed deallylation with phosphine as an added ligand was found to be 35 times faster than previously reported phosphine-free palladium-catalyzed depropargylation.
Next, the synthesis of tetrahydrofuran FR901464 analog is discussed. FR901464, a natural product splicing regulator with low nanomolar activity against various cancer cell lines. FR901464 analogs regulate the alternative splicing of the myeloid cell leukemia 1 pre-mRNA. We describe the synthesis of the first tetrahydrofuran FR901464 analog. The key step in the synthesis is electrophilic, N-bromosuccinimide-mediated cyclization. The new analog was shown to inhibit cancer cell growth with low micromolar potency, indicating the importance of the tetrahydropyran ring.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Pohorilets, Ivanna | IVP2@PITT.EDU | ivp2 | |
|
| ETD Committee: |
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| Date: |
24 February 2022 |
| Date Type: |
Publication |
| Defense Date: |
25 August 2021 |
| Approval Date: |
24 February 2022 |
| Submission Date: |
15 September 2021 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
300 |
| 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: |
Tsuji-Trost, deallylation, palladium, allyl, kinetics, FR901464 |
| Date Deposited: |
24 Feb 2023 06:00 |
| Last Modified: |
24 Feb 2024 06:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/41816 |
Available Versions of this Item
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Kinetic Study and Development of Ligand-Accelerated Clip Reactions and Synthesis of a Tetrahydrofuran Analog of FR901464. (deposited 24 Feb 2023 06:00)
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