DOI

10.17077/etd.9jb2s90u

Document Type

Dissertation

Date of Degree

Fall 2017

Degree Name

PhD (Doctor of Philosophy)

Degree In

Chemistry

First Advisor

Wiemer, David F.

First Committee Member

Geng, Lei

Second Committee Member

MacGillivray, Leonard R.

Third Committee Member

Pigge, Christopher

Fourth Committee Member

Small, Gary W.

Abstract

The pawhuskins and schweinfurthins are two classes of stilbene natural product compounds that exhibit interesting biological activity, and because of this they have been studied extensively in our lab through synthetic means.

The pawhuskins are a class of small molecule non-nitrogenous opioid receptor modulators that differ significantly in structure from the classical opioid receptor ligands.

Some of the natural schweinfurnthins show strong and differential antiproliferative behavior towards a variety of human cancer cell lines.

Prior to this research, a significant structure-activity relationship study conducted in our lab has produced a large library of analogues of both classes of compounds. The most potent of theses analogues have served as lead compounds in this study where the stilbene motif present in both classes was substituted with either an amide or triazole linkage.

For the new pawhuskin analogues, three of the amide isomers and a triazole isomer synthesized showed antagonist activity for the opioid growth factor (OGF)/opioid growth factor receptor (OGFR) axis which is involved in cellular and organ growth control. This cellular signaling mechanism is targeted by “low-dose” naltrexone therapy which is being tested clinically for multiple sclerosis, Crohn’s disease, cancer, and wound healing disorders. The compounds described here are the first selective small molecule ligands for the OGF/OGFR system and will serve as important leads and probes for further study.

For the new schweinfurthins analogues, all compounds synthesized retained antiproliferative activity against similar cancer cell lines to that of the natural compounds. The new amide analogues were produced in pairs only differing in the orientation of the amide linkage replacement for the stilbene motif. Signifigantly greater activity was seen for one orientation of the amide over the other.

The synthetic efforts towards all of these analogues will be described herein along with their intriguing biological properties.

Keywords

Amide isostere, Cancer, Opioid growth factor, Pawhuskins, Schweinfurthins, Triazole isostere

Pages

xix, 253 pages

Bibliography

Includes bibliographical references (pages 248-253).

Comments

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Copyright

Copyright © 2017 David Paul Stockdale

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Chemistry Commons

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