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Title: Design and synthesis of Combretastatin A-4 like chalcones and their analogues, and other anticancer agents
Author: Armitage, Edward Simon Marco
ISNI:       0000 0004 2751 1740
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2007
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This thesis covers work investigating the design, synthesis and evaluation of Combretastatin A-4 like chalcones and their analogues, and other anticancer agents. The first two chapters are an introduction to cancer chemotherapy and the development of tubulin as a target for chemotherapy. Chapter one includes information on cancer epidemiology, the history of cancer and the development of important cancer chemotherapy agents. While the second chapter describes the role of tubulin in mitosis, and the development of anticancer agents that target tubulin. The third chapter describes the background to the chalcone project, as well as the design and synthesis of new Combretastatin A-4 like chalcones and their analogues. To further the investigation of the substitution of the a-hydrogen of the chalcone with various groups, a series of a-arylchalcones was synthesized. The substitution of a-hydrogen with various aryl groups generally shows a significant increase in the anticancer activity of the chalcone. The effect of the conformation of the chalcone on its anticancer activity was also investigated by synthesizing two series of chalcone analogues which mimic the s-trans arrangement of chalcone, the indanones and indenones. Several of the indanones and indenones showed high levels of cytotoxicity with the CA-4 like indenone having an IC5o(K562) value of 0.019 uM. Chapter four looks at other chalcones with anticancer activity including the naturally occurring chalcone 4-hydroxyderricin, which has been isolated from the roots of Angelica keiskei and has shown to have anti-tumour promoting properties. As part of my PhD study the natural product 4-hydroxyderricin and a series of analogues was synthesized to investigate its anticancer activity. In chapter five I synthesized the anticancer agent KNK437 which has been shown to be a dose dependant inhibitor of the acquisition of thermotolerance in several different tumours. The study found that KNK437 sensitizes human leukaemia cells to the 17-allylamino-demethoxy geldanamycin induced apoptosis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available