Title page for ETD etd-09112008-083828


Type of Document Dissertation
Author Yang, Chao
Author's Email Address chaoyang@vt.edu
URN etd-09112008-083828
Title Syntheses and Bioactivities of Targeted and Conformationally Restrained Paclitaxel and Discodermolide Analogs
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Brewer, Karen J. Committee Member
Carlier, Paul R. Committee Member
Etzkorn, Felicia A. Committee Member
Gibson, Harry W. Committee Member
Kingston, David G. I. Committee Member
Keywords
  • tubulin-binding conformation
  • macrocyclic taxoids
  • T-taxol conformation
  • discodermolide
  • Taxol
  • drug targeting
  • thio-taxol
Date of Defense 2008-08-26
Availability unrestricted
Abstract
Paclitaxel was isolated from the bark of Taxus brevifolia 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 –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 Discodermia dissoluta in 1990. Similar to paclitaxel, discodermolide interacts with tubulin and stabilizes the microtubule in vivo. Studies aimed at understanding the biologically active conformation of discodermolide bound on –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.

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