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The Synthesis of 6,12-Guaianolide Analogs and Related Chemical Tools for Probing their Mechanism of NF-ĸB Inhibition

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 (Unpublished)

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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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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Wells, Sarah M.smp112@pitt.eduSMP112
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBrummond, Kay
Committee MemberFloreancig, Paul
Committee MemberGrabowski, Joseph
Committee MemberHarki, Daniel
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


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