Title page for ETD etd-07282002-181151


Type of Document Dissertation
Author Metaferia, Belhu B
Author's Email Address bmetafer@vt.edu
URN etd-07282002-181151
Title Synthesis of Taxol™ Analogs as Conformational Probes
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Kingston, David G. I. Committee Chair
Carlier, Paul R. Committee Member
Castagnoli, Neal Jr. Committee Member
Hanson, Brian E. Committee Member
Tanko, James M. Committee Member
Keywords
  • T-Taxol conformation
  • Tubulin
  • Taxol
  • Microtubules
  • Macrocyclic analogs
  • Anti-cancer agents
  • Ring-closing olefin metathesis
  • REDOR
  • ROESY
  • NAMFIS
Date of Defense 2002-07-18
Availability unrestricted
Abstract
Taxol™, isolated from the bark of Taxus brevifolia in the late 1960s, and the semisynthetic analog Taxotere™ have proven clinical importance for the treatment of ovarian and breast cancer. Taxol™ exerts its biological effect by binding to polymerized tubulin and stabilizing the resulting microtubules. Studies aimed at understanding the biologically active conformation of taxol and its binding environment on b-tubulin are described. This knowledge is important because it could lead to the design of structurally less complicated drugs with better efficacy and better bioavailability. Moreover, the information can be extended to other natural products that possess microtubule-stabilizing properties similar to Taxol™. In this work, the synthesis of a triply labeled taxol analog is described as well as REDOR studies of this compound complexed to tubulin are in progress. Macrocyclic analogs of taxol have been prepared and their biological activities were evaluated. Chemical modeling of these analogs and their activities agrees with the hypothesis that Taxol™ adopts T-shaped conformation. Difficulties were encountered with the key ring-closing metathesis strategy, suggesting that a more flexible and efficient macrocyclization method will be needed to synthesize additional macrocyclic analogs.
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  01-cover.PDF 10.03 Kb 00:00:02 00:00:01 00:00:01 < 00:00:01 < 00:00:01
  02-Abstract.PDF 21.97 Kb 00:00:06 00:00:03 00:00:02 00:00:01 < 00:00:01
  03-Literature.PDF 212.21 Kb 00:00:58 00:00:30 00:00:26 00:00:13 00:00:01
  04-Projects-Results.PDF 2.50 Mb 00:11:33 00:05:56 00:05:12 00:02:36 00:00:13
  05-Experimental.PDF 69.68 Kb 00:00:19 00:00:09 00:00:08 00:00:04 < 00:00:01
  06-Appendix-spectra.PDF 635.49 Kb 00:02:56 00:01:30 00:01:19 00:00:39 00:00:03
  07-Vita.PDF 5.19 Kb 00:00:01 < 00:00:01 < 00:00:01 < 00:00:01 < 00:00:01

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