Macquarie University
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Synthesis and conformational investigations of bioactive natural products and fluorinated analogues

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posted on 2022-03-28, 21:10 authored by Alpesh Ramanlal Patel
(-)-Balanol, a fungal metabolite from Verticillium balanoides, is a potent protein kinase C(PKC) inhibitor and has potential as an antitumor agent. However, it competitively inhibits other AGC protein kinases and lacks PKC isozyme specificity. The success from the first kinase drug, Gleevec, suggests that conformationally biased small molecules can lead to selective inhibition of tyrosine protein kinases. Fluorination has recently been utilized as a tool to conformationally tune the shape of molecules. The aim was to synthesize conformationally biased fluorinated balanol analogues and examine their PKA/PKC affinity and selectivity profiles (Figure 1). The structure activity relationship from this study may help understand conformational control in molecular recognition in general. The synthesis of mono-, di- and trifluoroazepanes was accomplished with unusual stereochemical outcomes due to neighbouring group participation. The conformational preferences of the mono-, di- and trifluoro azepanes were investigated using computational methods and J based analysis after detailed 2D NMR structure elucidations. The parent (-)-balanol and fluorinated balanol analogues were synthesized, and the analogues were subjected to binding affinity measurements with selected PKC isozymes and PKA.


Table of Contents

Chapter 1. Introduction -- Chapter 2. Diastereospecific fluorination of substituted azepanes -- Chapter 3. Conformational regulation of substituted azepanes through selective monofluorination -- Chapter 4. Conformational regulation of substituted azepand through fluorination -- Chapter 5. Cascade neighbouring group effect : potentially fluoronium-assisted aziridinium opening in solution -- Chapter 6. Synthesis and activity of fluorinated balanol analogues -- Chapter 7. Conclusions and future directions.


Includes bibliographical references Thesis by publication.

Awarding Institution

Macquarie University

Degree Type

Thesis PhD


PhD, Macquarie University, Faculty of Science and Engineering, Department of Chemistry and Biomolecular Sciences

Department, Centre or School

Department of Chemistry and Biomolecular Sciences

Year of Award


Principal Supervisor

Fei Liu

Additional Supervisor 1

Peter Karuso


Copyright Alpesh Ramanlal Patel 2013. Copyright disclaimer:




1 online resource (xix, 260 pages) illustrations (some colour)

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