Document Type

Dissertation

Date of Degree

Spring 2014

Degree Name

PhD (Doctor of Philosophy)

Degree In

Chemistry

First Advisor

David F. Wiemer

Abstract

The stilbene structure is part of many biologically active natural products, and these compounds can be attractive targets for chemical synthesis. A convergent synthetic design can be utilized in order to install the central olefinic moiety by way of organophosphorus compounds. This design has been employed to prepare a number of natural products, including the potent anti-cancer compounds known as the schweinfurthins and many analogues thereof. Not only do all these structures consist of a stilbenoid scaffold, but all are partially terpenoid in nature as well. Striking similarities to the schweinfurthins would become apparent following the isolation of a new group of compounds, which would later become known as the pawhuskins. In 2004, Belofsky and co-workers reported a small set of prenylated stilbenes that they named pawhuskins. Pawhuskins A-C were isolated from the common North American purple prairie clover (Dalea purpurea) collected near Pawhuska, Oklahoma. Belofsky's findings support an ethnomedical use, because the pawhuskins were shown to modulate opioid receptors through displacement of a nonselective radioactive antagonist (3[H]-naloxone) striatal tissue taken from rat brain. Pawhuskin A was the most potent member of the family, making it one of a small group of compounds that does not contain a basic nitrogen atom but that still exhibits effects on the opiate receptor system. This activity is surprising given the absence of the traditional pharmacophore, a 6-membered piperidine ring containing a basic nitrogen. In these studies, we will report the opioid receptor binding affinity and selectivity of pawhuskin A using a functional assay based on [35S]GTP-γ-S binding. Because of our well-established history of synthesizing prenylated stilbenes, and the unique biological activity of the pawhuskins, we embarked on a synthetic effort targeted at pawhuskin analogues. The preparation of sixteen analogues will be presented. The structure-activity relationship studies of twenty compounds correlated to illuminate more information on the novel pawhuskin pharmacophore will also be reported. Efforts toward preparation of more water-soluble structures similar to the pawhuskins will also be described. The interrelated studies involving pawhuskin analogue synthesis and elucidation of the novel pharmacophore, as well as interesting chemical findings, will be discussed in detail.

Keywords

opioid, pawhuskin, stilbene

Pages

xvii, 248 pages

Bibliography

Includes bibliographical references (pages 242-248).

Copyright

Copyright 2014 Alyssa Michelle Hartung

Included in

Chemistry Commons

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