Title page for ETD etd-71898-202047


Type of Document Dissertation
Author Yuan, Haiqing Jr.
Author's Email Address hyuan@vt.edu
URN etd-71898-202047
Title Studies on the Chemistry of Paclitaxel
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Calter, Michael A.
Castagnoli, Neal Jr.
Gandour, Richard D.
Taylor, Larry T.
Kingston, David G. I. Committee Chair
Keywords
  • analog
  • synthesis
  • Taxol®
  • Paclitaxel
  • SAR
Date of Defense 1998-08-11
Availability unrestricted
Abstract
STUDIES ON THE CHEMISTRY OF PACLITAXEL

HAIQING YUAN

(ABSTRACT)

Paclitaxel is a natural occurring diterpene alkaloid originally isolated from the bark of Taxus brevifolia. It is now one of the most important chemotherapeutic agents for clinical treatment of ovarian and breast cancers. Recent clinical trials have also shown paclitaxel's potential for the treatment of non-small-cell lung cancer, head and neck cancer, and other types of cancers. While tremendous chemical research efforts have been made in the past years, which established the fundamental structure-activity relationships of the paclitaxel molecule, and provided analogs for biochemical studies to elucidate the precise mechanism of action and for the development of second-generation agents, many areas remain to be explored.

In continuation of our efforts in the structure-activity relationships study of A-norpaclitaxel, five new analogs modified at the C-1 substituent and analogs with expanded B-ring or contracted C-ring have now been prepared. Preliminary biological studies indicated that the volume rather than functionality at the C-1 position plays a role in determining the anticancer activity by controlling the relative position of the tetracyclic ring system, which in turn controls the positions of the most critical functionalities such as the C-2 benzoyl, the C-4 acetate, and the C-13 side chain. The optimum conformation could possibly be modulated by ring contraction or expansion, as suggested by the improved activity of a B-lactone-A-norpaclitaxel analog.

Chemical investigations were also carried out in the C-6 and C-7 positions and led to the synthesis of five new analogs. Of particular importance, 6a-hydroxy-paclitaxel, the major human metabolite of paclitaxel, was synthesized for the first time through a C-7 epimerization reaction. The availability of the major human metabolite through synthesis makes it possible to perform in vivo biological investigations on the metabolite, and it also offers an important opportunity for the production of standard HPLC samples of the metabolites which could be useful in the clinical monitoring of paclitaxel's disposition in human patients.

Previous modifications at the C-4 position suggested that analogs with an acyl group other than an acetate at C-4 may exert similar activity to paclitaxel. Little was known, however, on the conformation-activity relationships of the C-4 position. In order to further explore the C-4 chemistry, a mild C-4 acylation method using acid as the acyl source was successfully developed. The new method was exemplified by the synthesis of water-soluble paclitaxel analogs with hydrophilic functional groups at the terminal of the C-4 acyl moiety. This method should be applicable to a variety of similar carboxylic acids and offer an alternative or even better approach for the preparation of C-4 modified paclitaxel analogs.

Lastly, in addition to the extension of paclitaxel analog library, specially designed analogs have been sought to probe the active conformation of paclitaxel. An analog that has a bridge to tie up the C-4 acyl group with an inert position would be useful for this purpose. With successful demonstration of the above C-4 acylation method, combined with the well established C-6 chemistry, the synthesis of such a novel C-4 and C-6 bridged paclitaxel analog was completed.

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