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Chemical studies of the C-4 position of baccatin III and taxol

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dc.contributor.authorNeidigh, Kurt Alanen
dc.contributor.committeechairKingston, David G. I.en
dc.contributor.committeememberCastagnoli, Neal Jr.en
dc.contributor.committeememberMerola, Joseph S.en
dc.contributor.committeememberTanko, James M.en
dc.contributor.committeememberBell, Harold M.en
dc.contributor.departmentChemistryen
dc.date.accessioned2014-03-14T21:21:39Zen
dc.date.adate2006-10-19en
dc.date.available2014-03-14T21:21:39Zen
dc.date.issued1995en
dc.date.rdate2006-10-19en
dc.date.sdate2006-10-19en
dc.description.abstractBecause of the efficacy of taxol against a wide variety of cancers, the demand for this drug has vastly increased during the last decade. Due to its limited natural supply, a number of alternative sources of taxol continue to be investigated. One approach toward alleviating the taxol supply problem is by the systematic investigation of the structure-activity relationships of the molecule, in order to establish the structural features and functionalities necessary for biological activity. Research efforts during the last decade have led to the establishment of the molecular domains and functionalilties which are crucial for biological activity, however at the inception of this work, the structure-activity relationships of the C-4 position of taxol were unknown. It was thus the major goal of this work to prepare 4-deacetyltaxol, in order to assess the importance of the C-4 acetate for overall activity, as well as to have a template molecule with which to begin studies aimed at determining the effect on activity rendered by replacement of the C-4 acetate with other acyl groups. Preliminary studies of the deacylation and reacylation of baccatin III were carried out in order to find conditions necessary for the preparation of 4-deacetylbaccatin III, and hence 4-deacetyltaxol. 4-Deacetyltaxol has now been prepared from baccatin III via two synthetic approaches and from taxol via one synthetic approach, and has been shown to be significantly less potent than taxol, suggesting that the C-4 acetate is necessary for biological activity. From the investigation of several potential synthetic approaches toward the formation of 4-acyltaxol analogs, one methodology has been developed which has allowed the preparation of 4-acyltaxol derivatives from baccatin III] or the more readily available 10- deacetylbaccatin III. This particular methodology can be extended to the preparation of other 4-acvitaxol or 4-acyltaxotere derivatives. Two C-5a halogenated oxetane ring-opened compounds have been prepared from a 4-deacetyltaxol derivative, offering the opportunity to investigate the potential effects on biological activity generated by modifications to the oxetane ring.en
dc.description.degreePh. D.en
dc.format.extentxvii, 312 leavesen
dc.format.mediumBTDen
dc.format.mimetypeapplication/pdfen
dc.identifier.otheretd-10192006-115617en
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-10192006-115617/en
dc.identifier.urihttp://hdl.handle.net/10919/40008en
dc.language.isoenen
dc.publisherVirginia Techen
dc.relation.haspartLD5655.V856_1995.N453.pdfen
dc.relation.isformatofOCLC# 36391835en
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subject.lccLD5655.V856 1995.N453en
dc.titleChemical studies of the C-4 position of baccatin III and taxolen
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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