Syntheses and Bioactivities of Targeted and Conformationally Restrained Paclitaxel and Discodermolide Analogs

Paclitaxel was isolated from the bark of <i>Taxus brevifolia</i> in the late 1960s. It exerts its biological effect by promoting tubulin polymerization and stabilizing the resulting microtubules. Paclitaxel has become one of the most important current drugs for the treatment of breast and ovarian cancers. Studies aimed at understanding the biologically active conformation of paclitaxel bound on β–tubulin are described. In this work, the synthesis of isotopically labeled taxol analogs is described and the REDOR studies of this compound complexed to tubulin agrees with the hypothesis that palictaxel adopts T-taxol conformation. Based on T-taxol conformation, macrocyclic analogs of taxol have been prepared and their biological activities were evaluated. The results show a direct evidence to support T-taxol conformation. (+) Discodermolide is a polyketide isolated from the Caribbean deep sea sponge <i>Discodermia dissoluta</i> in 1990. Similar to paclitaxel, discodermolide interacts with tubulin and stabilizes the microtubule <i>in vivo</i>. Studies aimed at understanding the biologically active conformation of discodermolide bound on β–tubulin are described. In this work, the synthesis of fluorescent labeled discodermolide analogs is described and their biological activities were evaluated. Synthetic approaches to fluorescent labeled and isotopically labeled discodermolide analogs discodermolide are also described.

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

2008

Author dc:creator

• Yang, Chao

Committee members dc:contributor.committeemember

• Etzkorn, Felicia A.
• Carlier, Paul R.
• Gibson, Harry W.
• Brewer, Karen J.
• Kingston, David G. I.

• tubulin-binding conformation
• macrocyclic taxoids
• T-taxol conformation
• discodermolide
• Taxol
• drug targeting
• thio-taxol

Statement dc:rights

• In Copyright

Licence dc:rights.uri

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

Dc Identifier Other

etd-09112008-083828

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/28942