Turner, Penelope A. (2012) Biologically active kigamicin analogues by sequential palladium catalysed C-O and C-C bond construction. PhD thesis, University of Warwick.

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Abstract

This thesis describes the study of the synthesis and biological evaluation of
analogues of the kigamicin natural products. Chapter One gives a background to
pancreatic cancer and explains the anti-austerity strategy for new therapeutics. It
then describes the kigamicins and their biological activity, focusing on why they are
thought to be clinically applicable. Other structurally related, tetrahydroxanthone
containing, natural products are also discussed.
Chapter Two focuses on the synthesis of the tetrahydroxanthone nucleus. Existing
methodology is initially utilised, before exploring formation of the
tetrahydroxanthone using milder, metal catalysed routes. Copper and palladium are
both explored for this transformation and an underlying uncatalysed process is
revealed and fully investigated. This methodology is extended to tandem catalysis
for the synthesis of 7-arylated tetrahydroxanthones through combination of this
chemistry with Suzuki-Miyaura couplings. Examples of Sonogashira and Heck
couplings as well as alternative substitution patterns, are also presented.
Chapter Three discusses the attempted synthesis of the fused rings of the
kigamicins. Our efforts towards suitable substrates are detailed.
Chapter Four outlines the anti-austerity assays established to evaluate the potency
and selectivity of analogues synthesised in Chapter Two. Kigamicin C is tested in
this assay to compare with literature values and validate our assay. The potency and
selectivity of our analogues are reported and compared to the natural product. The
anti-austerity effect of kibdelone C and analogues, is investigated for the first time.
Attempted isolation of the natural product is also described.
Chapter Five details the experimental procedures and characterisation data for the
novel compounds produced.

Item Type:	Thesis or Dissertation (PhD)
Subjects:	Q Science > QD Chemistry R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Library of Congress Subject Headings (LCSH):	Antineoplastic agents -- Research, Pancreas -- Cancer -- Treatment -- Research, Palladium, Organic compounds -- Synthesis
Official Date:	November 2012
Dates:	Date Event November 2012 Submitted
Institution:	University of Warwick
Theses Department:	Department of Chemistry
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Shipman, Michael
Sponsors:	Cancer Research UK
Extent:	237 leaves : illustrations.
Language:	eng

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