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Title: Biologically active kigamicin analogues by sequential palladium catalysed C-O and C-C bond construction
Author: Turner, Penelope A.
ISNI:       0000 0004 2748 7656
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2012
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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.
Supervisor: Not available Sponsor: Cancer Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD Chemistry ; RC0254 Neoplasms. Tumors. Oncology (including Cancer)