eprintid: 28636
rev_number: 22
userid: 5641
dir: disk0/00/02/86/36
datestamp: 2016-10-03 20:19:55
lastmod: 2017-10-03 05:15:07
status_changed: 2016-10-03 20:19:55
type: thesis_degree
metadata_visibility: show
contact_email: sarahwells723@gmail.com
item_issues_count: 0
eprint_status: archive
creators_name: Wells, Sarah M.
creators_email: smp112@pitt.edu
creators_id: SMP112
title: The Synthesis of 6,12-Guaianolide Analogs and Related Chemical Tools for Probing their Mechanism of NF-ĸB Inhibition
ispublished: unpub
divisions: sch_as_chemistry
full_text_status: public
keywords: guaianolides
allenic Pauson-Khand reaction
alkyne probes
NF-ĸB Inhibition
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.
date: 2016-10-03
date_type: published
pages: 361
institution: University of Pittsburgh
refereed: TRUE
etdcommittee_type: committee_chair
etdcommittee_type: committee_member
etdcommittee_type: committee_member
etdcommittee_type: committee_member
etdcommittee_name: Brummond, Kay M
etdcommittee_name: Floreancig, Paul E
etdcommittee_name: Grabowski, Joseph J
etdcommittee_name: Harki, Daniel A
etdcommittee_email: kbrummon@pitt.edu
etdcommittee_email: florean@pitt.edu
etdcommittee_email: joeg@pitt.edu
etdcommittee_email: daharki@umn.edu
etd_defense_date: 2016-07-22
etd_approval_date: 2016-10-03
etd_submission_date: 2016-07-15
etd_release_date: 2016-10-03
etd_access_restriction: 1_year
etd_patent_pending: FALSE
thesis_type: dissertation
degree: PhD
citation:   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)  
document_url: http://d-scholarship-dev.library.pitt.edu/28636/1/WellsSM_ETD2016_3.pdf