Studies of paclitaxel analogs modified in ring C

The structurally novel diterpenoid paclitaxel (Taxol®), originally isolated from <i>Taxus brevifolia</i>, is one of the most promising new anticancer drugs. Its structural complexity and unique biological activity have provided the impetus for a number of structure-activity relationship (SAR) studies for the last twenty years, with the aim of developing analogs with improved bioactivity. Because of the absence of information on the structure-activity relationship of the C-6 position and the ring C skeleton of paclitaxel, it was goal of this research to synthesize paclitaxel analogs modified in ring C in order to evaluate the effects of these modifications on biological activity and to reveal the chemistry of paclitaxel. The inactivity of the C-6 methylene group towards chemical modifications has been overcome by the formation of a double bond at the C- 6 and C-7 positions. Modification of the C-6 position has been achieved for the first time and over 20 new paclitaxel analogs modified at both the C-6 and C-7 positions have been synthesized. Biological evaluation of these compounds reveal that the C-6 and C-7 positions do not play significant roles in the biological activity of paclitaxel, although the two deoxygenated paclitaxel analogs, 7-deoxy-6α-hydroxypaclitaxel and 7,lO-dideoxy-6ahydroxypaclitaxel, were found to be more active than paclitaxel. Modification of the ring C skeleton has been accomplished for the first time, and several new C-<i>nor</i>-paclitaxel analogs have been synthesized. Biological evaluation showed that these C-<i>nor</i>-paclitaxel analogs were less active than paclitaxel, indicating that the ring C skeleton plays a crucial role in the biological activity of paclitaxel. Biological evaluation also showed that all oxetane ring-opened paditaxel analogs were essentially inactive. These results indicate that changes in the size and conformation of ring C and the attached oxetane ring make a significant contribution to the activity of paclitaxel.

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

1996

Author dc:creator

• Liang, Xian

Chair dc:contributor.committeechair

• Kingston, David G. I.

Committee members dc:contributor.committeemember

• Bell, Harold M.
• Castagnoli, Neal Jr.
• Hanson, Brian E.
• Tanko, James M.

• anticancer agent
• pactilaxel
• modification
• ring C

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-08082007-161932

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/39115