Design, Syntheses and Biological Activities of Paclitaxel Analogs

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dc.contributor.authorZhao, Jieluen
dc.contributor.committeechairKingston, David G. I.en
dc.contributor.committeememberDorn, Harry C.en
dc.contributor.committeememberEtzkorn, Felicia A.en
dc.contributor.committeememberGandour, Richard D.en
dc.contributor.committeememberCarlier, Paul R.en
dc.contributor.departmentChemistryen
dc.date.accessioned2017-04-06T15:44:22Zen
dc.date.adate2011-05-03en
dc.date.available2017-04-06T15:44:22Zen
dc.date.issued2011-01-31en
dc.date.rdate2016-10-24en
dc.date.sdate2011-02-21en
dc.description.abstractThe conformation of paclitaxel in the bound state on the protein has been proposed to be the T-taxol conformation, and paclitaxel analogs constrained to the T-taxol conformation proved to be significantly more active than paclitaxel in both cytotoxicity and tubulin polymerization assays, thus validating the T-taxol conformation as the tubulin-binding conformation. In this work, eight compounds containing an aza-tricyclic moiety as a mimic of the baccatin core of paclitaxel have been designed and synthesized as water-soluble simplified paclitaxel analogs, among which 3.50-3.52 and 3.55 were conformationally constrained analogs designed to bind to the paclitaxel binding site of tubulin, based on their similarity to the T-taxol conformation. The open-chain analogs 3.41-3.43 and 3.57 and the bridged analogs 3.50-3.52 and 3.55 were evaluated for their antiproliferative activities against the A2780 cell lines. Analogs 3.50-3.52 and 3.55 which were designed to adopt the T-taxol conformation showed similar antiproliferative activities compared to their open-chain counterparts. They were all much less active than paclitaxel. In the second project, a series of paclitaxel analogs with various thio-containing linkers at C-2′ and C-7 positions were designed and synthesized in our lab. These analogs were attached to the surfaces of gold nanoparticles by CytImmune Sciences for the development of mutifunctional tumor-targeting agents. The native analogs and the gold bound analogs were evaluated for their antiproliferative activities against the A2780 cell line. All the compounds tested showed comparable or better activities than paclitaxel. Stability studies were performed for selected analogs in hydrolysis buffer, which showed that the analogs released paclitaxel in buffer over time. In the third project, the synthesis of a conformationally constrained paclitaxel analog which was designed to mimic the REDOR-taxol conformation was attempted. Two synthetic routes were tried and significant progress was made toward the synthesis of the conformationally constrained analog. However, both of the current synthetic routes failed to produce the key intermediate that would serve as the precursor for a ring-closing metathesis reaction to furnish the macrocyclic ring.en
dc.description.degreePh. D.en
dc.identifier.otheretd-02212011-154633en
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-02212011-154633/en
dc.identifier.urihttp://hdl.handle.net/10919/77272en
dc.language.isoen_USen
dc.publisherVirginia Techen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectT-taxolen
dc.subjecttubulinen
dc.subjectbioactive conformationen
dc.subjectmicrotubulesen
dc.subjectthiolated paclitaxelen
dc.subjectgold nanoparticlesen
dc.subjectconformationally constrained paclitaxelen
dc.subjectsimplified paclitaxelen
dc.titleDesign, Syntheses and Biological Activities of Paclitaxel Analogsen
dc.typeDissertationen
dc.type.dcmitypeTexten
thesis.degree.disciplineChemistryen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.leveldoctoralen
thesis.degree.namePh. D.en

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