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Design and synthesis of combretastatin A-1 analogs, small molecule vascular disrupting agents, and bioreductive triggers as potential therapeutic agents for the treatment of cancer.

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dc.contributor.advisor Pinney, Kevin G.
dc.contributor.author Nguyen, Benson Lee.
dc.contributor.other Baylor University. Dept. of Chemistry and Biochemistry. en
dc.date.copyright 2010-12
dc.identifier.uri http://hdl.handle.net/2104/8092
dc.description.abstract Cancer is the second leading cause of death in the United States with over 550,000 deaths in 2009 and a devastating 7.9 million deaths worldwide in 2007. Vascular disrupting agents (VDAs) represent a novel method developed for the treatment of cancer. VDAs, such as combretastatin A1 phosphate (CA1P, Oxi4503) and combretastatin A4 phosphate (CA4P, ZybrestatTM, fosbretabulin), after undergoing phosphate cleavage by non-specific phosphatase enzymes, selectively bind to the colchicine site on tubulin, disrupting tubulin polymerization. The integrity of the microtubules that form the cytoskeleton of the endothelial cells that line the tumor vasculature is altered, causing tumor vasculature occlusion and collapse, thus preventing nutrients and oxygen from reaching the tumor. This leads to severe tumor hypoxia, tumor perfusion regression and tumor necrosis. A series of anticancer agents were designed to incorporate a VDA or cytotoxic agent linked to a bioreductive drug to form a bioreductive prodrug conjugate. When the bioreductive portion of the molecular conjugate is reduced, the linkage between the VDA and the bioreductive drug is broken, releasing the VDA in its active form to act upon the tumor vasculature. The reduced bioreductive drug becomes a chemotherapeutic agent that can damage the tumor cells. CA1 is a potent inhibitor of tubulin polymerization and it has been shown that CA1 undergoes a second mechanism of action against tumors. CA1 incorporates an ortho diphenolic moiety that can be oxidized to form an ortho quinone that can damage DNA. To further elucidate the biological mechanism of action of CA1, a synthetic methodology was developed to incorporate a radioisotope at a metabolically stable position. In addition, a total synthesis was designed to prepare each of the combretastatin A1 monophosphates in regioisomeric pure form. en
dc.rights Baylor University theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. Contact librarywebmaster@baylor.edu for inquiries about permission. en
dc.subject Combretastatin A-1 analogs. en
dc.subject Small molecule vascular disrupting agents. en
dc.subject Bioreductive triggers. en
dc.subject Cancer treatment. en
dc.subject Chemistry. en
dc.title Design and synthesis of combretastatin A-1 analogs, small molecule vascular disrupting agents, and bioreductive triggers as potential therapeutic agents for the treatment of cancer. en
dc.type Thesis en
dc.description.degree Ph.D. en
dc.rights.accessrights Worldwide access. en
dc.rights.accessrights Access changed 3/18/13.
dc.contributor.department Chemistry and Biochemistry. en


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