Wells, Sarah M.
(2016)
The Synthesis of 6,12-Guaianolide Analogs and Related Chemical Tools for Probing their Mechanism of NF-ĸB Inhibition.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Guaianolides, the largest class of sesquiterpene lactones, possess a wide range of biological activities, particularly in the areas of anti-inflammation and anticancer. The allenic Pauson-Khand reaction (APKR) is a rhodium (I) catalyzed [2 + 2 + 1] cyclocarbonylation reaction of allene-ynes and has been established as a viable methodology for accessing the guaianolide 5,7,5-tricyclic framework. However, allene-yne precursors with methyl substituted allenes and alkynes have been poorly tolerated. Optimization of high dilution APKR conditions is described for these methyl substituted allene-ynes, which give direct access to C4 and C10 methyl substituted bicycle[5.3.0]decadienones, consistent with the guaianolide framework.
This APKR approach was also applied to continuing the synthesis of highly oxygenated guaianolide analogs, capable of inhibiting NF-ĸB. The α-methylene-γ-butyrolactone moiety is incorporated into allene-yne tether prior to the APKR. Given the potent NF-ĸB inhibitory properties demonstrated by our analogs, derivatives were synthesized in effort to examine the biological mechanism of inhibition. Installation of alkyne ligation handles onto the base-sensitive guaianolide analogs, for use in biomechanistic studies, was achieved using the acid mediated Nicholas reaction. This method was also established for the general installation of alkyne ligation handles onto hydroxyl, sulfhydryl, amino, and carboxyl groups. Synthesis and biological evaluation of an α-methyl-γ-butyrolactone guaianolide analog established the importance of the α-methylene-γ-butyrolactone moiety for potent NF-ĸB inhibition.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
3 October 2016 |
| Date Type: |
Publication |
| Defense Date: |
22 July 2016 |
| Approval Date: |
3 October 2016 |
| Submission Date: |
15 July 2016 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
361 |
| 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: |
guaianolides
allenic Pauson-Khand reaction
alkyne probes
NF-ĸB Inhibition |
| Date Deposited: |
03 Oct 2016 20:19 |
| Last Modified: |
03 Oct 2017 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/28636 |
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