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

Because 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.

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

• Neidigh, Kurt Alan

Chair dc:contributor.committeechair

• Kingston, David G. I.

Committee members dc:contributor.committeemember

• Castagnoli, Neal Jr.
• Merola, Joseph S.
• Tanko, James M.
• Bell, Harold M.

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-10192006-115617

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/40008