The chemistry of cephalomannine

Cephalomannine 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.

Name thesis:degree_name

Ph. D.

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Chemistry

Department dc:contributor.department

Chemistry

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

1995

Author dc:creator

• Molinero, Anthony A.

Chair dc:contributor.committeechair

• Kingston, David G. I.

Committee members dc:contributor.committeemember

• Tanko, James M.
• Hanson, Brian E.
• Wolfe, James F.
• Brewer, Karen J.

Statement dc:rights

• In Copyright

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Language dc:language.iso

en

Dc Identifier Other

etd-06062008-163401

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/38228