Dempe, Daniel P.
(2022)
α-Methylene-γ-Lactams: Thiol Reactivity, Bioactivity, and Applications Towards Targeted Covalent Inhibitors.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The α-methylene-γ-lactam offers promise as a new warhead for the development of targeted covalent inhibitors. However, a full understanding of the factors governing its electrophilic reactivity are still needed to promote the development of drug candidates utilizing this motif. Herein we take steps to establish the therapeutic potential of the α-methylene-γ-lactam warhead by measuring: thiol reactivity, NF-κB inhibitory activity, and cytotoxicity of guaianolide analogs containing this electrophilic motif. When compared to a highly reactive natural product containing an α-methylene-γ-lactone, these lactams exhibited muted thiol reactivity and cytotoxicity –modulated by the N-substituent– while maintaining good bioactivity. To determine the electronic effects of the N-substituent, a series of N-arylated 3-methylene-2-pyrrolidinones, differing only in the substituents on the aryl group, were prepared and the thiol reactivities measured. The rate constants correlated strongly with both Hammett parameters of the aryl substituents and with the computed activation barriers. Lastly, we synthesized a corresponding series of N-substituted α-methylene-γ-lactams installed within the framework of a bioactive guaianolide analog. To determine the effects of guaianolide structure on warhead reactivity, thiol reactivities of these compounds were measured. A good correlation between the electronic character of the N-substituent and the thiol reactivity is observed within a cis- or trans- annulated isomeric series of compounds. Trans-annulated compounds exhibited a ca. 10-fold increase in reactivity relative to both the cis-annulated compounds and the N-arylated 3-methylene-2-pyrrolidinones.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
30 April 2022 |
| Date Type: |
Publication |
| Defense Date: |
16 February 2022 |
| Approval Date: |
25 October 2024 |
| Submission Date: |
16 March 2022 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
264 |
| 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: |
Thiol Reactivity, Guaianolides, Targeted Covalent Inhibitors |
| Date Deposited: |
25 Oct 2024 19:13 |
| Last Modified: |
28 Oct 2024 12:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/42371 |
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