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DESIGN AND SYNTHESIS OF NOVEL ANTI-INFLAMMATORY
LIPID MEDIATORS AND ANTICANCER SMALL MOLECULES
by
Jasim Uddin
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(CHEMISTRY)
May 2008
Copyright 2008 Jasim Uddin
Object Description
| Title | Design and synthesis of novel anti-inflammatory lipid mediators and anticancer small molecules |
| Author | Uddin, Jasim |
| Author email | muddin@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Chemistry |
| School | College of Letters, Arts and Sciences |
| Date defended/completed | 2007-12-12 |
| Date submitted | 2008 |
| Restricted until | Unrestricted |
| Date published | 2008-04-29 |
| Advisor (committee chair) | Petasis, Nicos A. |
| Advisor (committee member) |
Schönthal, Axel H. Bau, Robert Periana, Roy A. |
| Abstract | This dissertation deals with two distinct projects. First -- Design and synthesis of novel anti-inflammatory lipid mediators -- It is well documented that omega-3 polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) display beneficial actions in many human diseases. The underlying molecular mechanism for these actions remains of tremendous interest, but yet to be established until recently Serhan and colleagues identified a novel class of lipid mediators generated from EPA and DHA during the resolution phase of inflammation via cell-cell interactions that displayed potent anti-inflammatory, pro-resolving activities. The lipid mediators derived from EPA are designated as E-series of resolvins such as RvE1, and the lipid mediators generated from DHA are denoted as D-series of resolvins such as RvD1, RvD2, RvD3 and RvD4. In addition, aspirin triggers the endogenous formation of epimeric series of D-series of resolvins named aspirin-triggered resolvins such as AT-RvD1, AT-RvD2, AT-RvD3 and AT-RvD4. These lipid mediators are generated in very minute quantities in stereochemically pure form and possess potent anti-inflammatory, pro-resolving bioactions.; The first part of this dissertation deals with the first asymmetric total syntheses of these lipid mediators for their complete stereochemical assignments, and for further biological studies. The first asymmetric total syntheses of RvE1, RvD1, AT-RvD1, 7S-RvD2, 7R-RvD2 were accomplished, and efforts towards the total syntheses of RvD3, AT-RvD3, RvD4 and AT-RvD4 described. A highly convergent and practical approach heavily relied on Pd0/CuI medicated cross-coupling, Wittig, and modified Wittig reactions were employed to embark these molecules in their stereochemically pure form. The absolute stereochemical assignments of RvE1, RvD1 and AT-RvD1 were established by matching the physical and biological properties of stereochemically pure synthetic one with their biogenic counterparts. The metabolic inactivation pathways of RvE1, RvD1 and AT-RvD1 were also investigated, and described here in this dissertation. The elucidation of the biochemical inactivation pathways of these lipid mediators including their arachidonic acid derived cousins lipoxins provided the rationale for the design of their biostable analogs. A number of analogs have been designed, and synthesized, and the designed biostable analogs were found to be superior to their natural counterparts. Our efforts provided the basis for the development of potential new therapeutics for the treatment of inflammation and inflammation associated diseases.; Second -- Design and synthesis of anticancer small molecules -- Celecoxib (Celebrex®) is a non-steroidal anti-inflammatory drug (NSAID), which is widely used for the treatment of patients with arthritis and osteoarthritis. It is unique among other COX-2 inhibitors because of its ability to induce cancer cell death. Despite promising results, the underlying molecular mechanisms for its anticancer properties are poorly understood, and somewhat controversial. To evaluate any apparent involvement of COX-2 for its anticancer activity, we have designed a close structural analog of celecoxib, named 2,5-dimethyl celecoxib (DMC), which is not a COX-2 inhibitor. The synthesis of DMC and its structural analogs were discussed in this dissertation. Our collaborator performed a series of experiments both in vivo and in vitro, and found that DMC potently mimics the all anti-tumor activities of celecoxib and finally came to a conclusion that celecoxib does its anti-proliferative and pro-apoptotic effects without any apparent involvement of COX-2. |
| Keyword | total sythesis; lipid mediators; inflammation; anticancer; small molecules |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Type | texts |
| Legacy record ID | usctheses-m1211 |
| Rights | Uddin, Jasim |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Uddin-20080429 |
| Archival file | uscthesesreloadpub_Volume14/etd-Uddin-20080429.pdf |
Description
| Title | Page 1 |
| Full text | DESIGN AND SYNTHESIS OF NOVEL ANTI-INFLAMMATORY LIPID MEDIATORS AND ANTICANCER SMALL MOLECULES by Jasim Uddin A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (CHEMISTRY) May 2008 Copyright 2008 Jasim Uddin |
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