Syntheses and Bioactivities of Targeted and Conformationally Restrained Paclitaxel and Discodermolide Analogs

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dc.contributor.authorYang, Chaoen
dc.contributor.committeememberEtzkorn, Felicia A.en
dc.contributor.committeememberCarlier, Paul R.en
dc.contributor.committeememberGibson, Harry W.en
dc.contributor.committeememberBrewer, Karen J.en
dc.contributor.committeememberKingston, David G. I.en
dc.contributor.departmentChemistryen
dc.date.accessioned2014-03-14T20:16:09Zen
dc.date.adate2008-10-17en
dc.date.available2014-03-14T20:16:09Zen
dc.date.issued2008-08-26en
dc.date.rdate2011-09-05en
dc.date.sdate2008-09-11en
dc.description.abstractPaclitaxel was isolated from the bark of <i>Taxus brevifolia</i> in the late 1960s. It exerts its biological effect by promoting tubulin polymerization and stabilizing the resulting microtubules. Paclitaxel has become one of the most important current drugs for the treatment of breast and ovarian cancers. Studies aimed at understanding the biologically active conformation of paclitaxel bound on β–tubulin are described. In this work, the synthesis of isotopically labeled taxol analogs is described and the REDOR studies of this compound complexed to tubulin agrees with the hypothesis that palictaxel adopts T-taxol conformation. Based on T-taxol conformation, macrocyclic analogs of taxol have been prepared and their biological activities were evaluated. The results show a direct evidence to support T-taxol conformation. (+) Discodermolide is a polyketide isolated from the Caribbean deep sea sponge <i>Discodermia dissoluta</i> in 1990. Similar to paclitaxel, discodermolide interacts with tubulin and stabilizes the microtubule <i>in vivo</i>. Studies aimed at understanding the biologically active conformation of discodermolide bound on β–tubulin are described. In this work, the synthesis of fluorescent labeled discodermolide analogs is described and their biological activities were evaluated. Synthetic approaches to fluorescent labeled and isotopically labeled discodermolide analogs discodermolide are also described.en
dc.description.degreePh. D.en
dc.identifier.otheretd-09112008-083828en
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-09112008-083828/en
dc.identifier.urihttp://hdl.handle.net/10919/28942en
dc.publisherVirginia Techen
dc.relation.haspartDissertation.pdfen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjecttubulin-binding conformationen
dc.subjectmacrocyclic taxoidsen
dc.subjectT-taxol conformationen
dc.subjectdiscodermolideen
dc.subjectTaxolen
dc.subjectdrug targetingen
dc.subjectthio-taxolen
dc.titleSyntheses and Bioactivities of Targeted and Conformationally Restrained Paclitaxel and Discodermolide Analogsen
dc.typeDissertationen
thesis.degree.disciplineChemistryen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.leveldoctoralen
thesis.degree.namePh. D.en

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