Design, Synthesis and Biological Evaluation of C4-C9 Bridged Epothilone Analogs Open Access

Jiang, Yi (2011)

Permanent URL: https://etd.library.emory.edu/concern/etds/08612p12k?locale=en
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Abstract

C4-C9 bridged epothilone analogs were computationally designed to derive experimental evidence for the recently proposed EC binding model of epothilone A in the tubulin binding site. Two generations of synthetic routes toward the target molecule were devised and implemented. The first generation synthesis based on macrolactonization and ring-closing metathesis failed to deliver the desired target molecule presumably due to the difficulty of esterification of the C9-OH group. The second generation synthesis based on B-alkyl Suzuki coupling and macrolactonization provided the precursor to the desired C4-C9 bridged epthilone D analog. However, upon global deprotection, an unexpected Michael addition between the C-3 OH group and the unsaturated macrolactone bridge led to formation of additional THF ring in the resulting bridged epothilone D and B analogs. The biological evaluation of the two bridged epothilone analogs indicated that they are 150 and 300 times less active than Taxol®, respectively.

Design, Synthesis and Biological Evaluation of C4-C9 Bridged Epothilone Analogs

By
Yi Jiang
M.S. Fudan University, 2004
B.S. Anhui University of Science and Technology, 2000
Advisor: Dennis C. Liotta, Ph.D.
A dissertation submitted to the Faculty of the
James T. Laney School of Graduate Studies of Emory University
in partial fulfil ment of the requirements for the degree of
Doctor of Philosophy
in Chemistry
2011

Table of Contents

Table of Contents

1.1.

Introduction and Background.....................................................................1
1.1.1 Microtubules: A Validated Target for Anti-Cancer Drugs....................1
1.1.2 Epothilones: New Agent for Anti-Cancer Drugs Targeting
Microtubules……………………………………………………………….6
1.1.3 SAR Studies of Epothilones..............................................................10
1.1.4 Bioactive Conformation of Epothilones.............................................17
1.2. Design and Synthesis of C4-C9 Bridged Epothilones..............................20
1.2.1 Design Rationale...............................................................................20
1.2.2 First Generation Synthesis via Ring Closure Metathesis..................24
1.2.3 Second Generation Synthesis via Suzuki Coupling..........................33
1.3. Biological Evaluation of Analogs..............................................................48
1.4. Conclusion...............................................................................................49
1.5. Experimental Section...............................................................................50
1.5.1. Chemistry..........................................................................................50
1.5.2. Molecular Modeling……………..……….........……………………….123
1.5.3. Cytotoxicity Assay...........................................................................113

1.5.4. X-ray Crystallography Data.............................................................125

1.6.
References.............................................................................................176










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