Structural Modifications of OXi8006 Leading to New Indole-Based Anti-Cancer Agents

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dc.contributor.advisorPinney, Kevin G.
dc.contributor.authorHor, Priscilla
dc.contributor.departmentChemistry and Biochemistry.en_US
dc.contributor.schoolsHonors College.en_US
dc.date.accessioned2012-05-04T21:45:39Z
dc.date.available2012-05-04T21:45:39Z
dc.date.copyright2012
dc.date.issued2012-05-04
dc.description.abstractA promising method for treating cancer involves selectively targeting the tumor vascular network. Tumor vascular is characterized as a disorganized and convoluted network of microvessels, in contrast to normal tissue vasculature, presenting an ideal target for small molecule intervention. Small-molecule anti-cancer agents, known as vascular disrupting agents (VDAs), function by damaging existing tumor vasculature through an essential binding interaction at the dynamic tubulin-protein system effecting vessel occlusion and collapse. This selective binding ultimately deprives tumors of vital nutrients and oxygen necessary for growth resulting in hypoxia and tumor necrosis. A particular benchmark VDA isolated from the bark of the South African bush willow tree Combretum caffrum is combretastatin A-4 (CA4). This compound demonstrates exceptional inhibition of tubulin assembly. Previous investigations in the Pinney Lab led to the development of an indole-based VDA modeled after CA4 known as OXi8006. OXi8006 exhibits inhibition of tubulin polymerization comparable to CA4 and demonstrates strong cytotoxicity against human cancer cell lines. In an effort to better understand the biochemical mechanisms of action and fully evaluate the biological activity of OXi8006 sufficient amounts of the compound are necessary. In addition to the resynthesis of OXi8006, structural modifications on the indole scaffold will provide insight into the biological activity and tubulin assembly inhibition with respect to regioselective functionalizations. In addition, modified analogues of OXi8006 can lead to the discovery of new potent VDAs. Herein, we report the total synthesis and biological evaluation of OXi8006 and a diphenolic derivative. Furthermore, the preparation of advanced intermediates en route to future diversely functionalized analogues is presented.en_US
dc.identifier.urihttp://hdl.handle.net/2104/8376
dc.language.isoen_USen_US
dc.rightsBaylor University projects 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 libraryquestions@baylor.edu for inquiries about permission.en_US
dc.rights.accessrightsWorldwide access.en_US
dc.rights.accessrightsAccess changed 12/16/14.
dc.subjectVascular Disrupting Agents.en_US
dc.subjectOrganic Synthesis.en_US
dc.subjectAnti-Cancer Agentsen_US
dc.subjectIndole-Based VDAsen_US
dc.titleStructural Modifications of OXi8006 Leading to New Indole-Based Anti-Cancer Agentsen_US
dc.typeThesisen_US

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