The chemistry of cephalomannine

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dc.contributor.authorMolinero, Anthony A.en
dc.contributor.committeechairKingston, David G. I.en
dc.contributor.committeememberTanko, James M.en
dc.contributor.committeememberHanson, Brian E.en
dc.contributor.committeememberWolfe, James F.en
dc.contributor.committeememberBrewer, Karen J.en
dc.contributor.departmentChemistryen
dc.date.accessioned2014-03-14T21:13:28Zen
dc.date.adate2008-06-06en
dc.date.available2014-03-14T21:13:28Zen
dc.date.issued1995en
dc.date.rdate2008-06-06en
dc.date.sdate2008-06-06en
dc.description.abstractCephalomannine is a naturally occurring taxane diterpenoid closely related to the potent anticancer agent Taxol. Three aspects of its chemistry were examined. First, cephalomannine was converted to Taxol. This conversion was accomplished by the reaction of a 2'- benzoyl-7-Troc cephalomannine/Taxol mixture with oxalyl chloride to generate a common oxamic acid intermediate. Treatment of this intermediate with diphenylcarbodiimide cleaved the N-oxalyl group which resulted in a spontaneous transfer of the 2'-benzoyl group to the 3'-N position. Deprotection of the 7-Troc group afforded Taxol. Second, a number of 3'-N-acyl cephalomannine and Taxol analogs were prepared and their biological activity determined. The N-tigloyl group of cephalomannine was modified by oxygenation and halogenation to yield several cephalomannine derivatives. The Taxol analogs were prepared by coupling a protected side chain to baccatin III, deprotecting, and acylating the resulting free amine. This methodology was used to prepare several oxalyl and halogenated analogs as well as N-(phenylglyoxyl) and N-crotonyl derivatives. One derivative in particular, N-debenzoyl-N-(2"-bromopropenoyl)taxol, was found to be significantly more active than Taxol. Third, Taxotere, 10- acetyltaxotere, N-debenzoyl-N-(phenoxyacetyl)taxol, and the cephalomannine diol were synthetically prepared for testing in several tubulin polymerization systems. Earlier studies had shown that some Taxol analogs had the ability to stabilize tubulin polymers to cold, but failed to induce assembly as does Taxol. The compounds prepared were used to investigate the differences and this led to the conclusion that the hypernucleation of tubulin assembly and polymer stabilization observed with Taxol represent two distinct properties of the drug.en
dc.description.degreePh. D.en
dc.format.extentxiii, 267 leavesen
dc.format.mediumBTDen
dc.format.mimetypeapplication/pdfen
dc.identifier.otheretd-06062008-163401en
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-06062008-163401/en
dc.identifier.urihttp://hdl.handle.net/10919/38228en
dc.language.isoenen
dc.publisherVirginia Techen
dc.relation.haspartLD5655.V856_1995.M655.pdfen
dc.relation.isformatofOCLC# 34050693en
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subject.lccLD5655.V856 1995.M655en
dc.titleThe chemistry of cephalomannineen
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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