In order to investigate the structural features responsible for the cytotoxicity of the naturally occurring lignan nordihydroguaiaretic acid, the synthesis of four structural analogues of NDGA is proposed for the purpose of studying their oxidative metabolism. One analogue in particular (1), a mono-catechol analogue, is successfully synthesized employing a double Stobbe condensation approach. Following synthesis of this compound a series of oxidation experiments is performed consisting of: incubation in rat liver microsomes with and without the trapping agent glutathione (GSH), oxidation with mushroom tyrosinase, oxidation with silver oxide, and oxidation with horseradish peroxidase. Results are analyzed via HPLC and UPLC-MS. It is found that 1 does not autoxidize at pH 7.4 as NDGA does. Two products are produced during incubation of 1 in rat liver microsomes with UPLC-ESI(-)-MS results giving m/z of 879.2 and 574.18. This is consistent with 1 plus 2 GSH and 1 plus 1 GSH respectively; confirming 1 will oxidize to an electrophilic moiety. Oxidation with mushroom tyrosinase is found to produce high levels of product two with m/z 574.2. Oxidation with horseradish peroxidase is found to produce high levels of the m/z 879.2 product. Silver Oxide produced multiple products rather than the expected one major product, but most are found to be inconsistent with the products seen during rat liver microsomal incubation, and are not pursued.
| Identifer | oai:union.ndltd.org:USASK/oai:usask.ca:etd-05192010-134624 |
| Date | 01 June 2010 |
| Creators | Maloney, Katherine Ann |
| Contributors | Berry, Mark, Palmer, David, Majewski, Marek, Alcorn, Jane, Krol, Ed S. |
| Publisher | University of Saskatchewan |
| Source Sets | University of Saskatchewan Library |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://library.usask.ca/theses/available/etd-05192010-134624/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Saskatchewan or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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