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Title: Invention of novel catalytic cascade reactions and their application to anticancer drug targets
Author: Groome , Nigel Mark
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2011
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The main body of this thesis comprises four chapters: Chapter One serves as an introduction. The first two thirds deals with cell signalling cascades, focusing particularly upon protein kinases and the roles that their dysfunction play in cancerous processes and upon the methods employed to inhibit them in a bid to counter these processes. Kinase inhibition by small molecules is a very active area of research and notable clinical successes have been achieved. The last portion of the chapter addresses some of the issues surrounding .drug discovery, and ends by stating the author's intention to utilise novel transition metal catalysis to access potential anticancer compounds, to test these compounds against cancer cell lines in vitro and to study their interactions with the active sites of cell signalling proteins known to be mutated in these same cancers in silica. After a brief introductory section dealing with relevant chemistry, Chapter Two describes the author's work with the arylallylation of purine derivatives via a 3-component palladium-catalysed cascade developed within the Grigg group, and the subsequent in vitro testing against the colon cancer cell line HCT116. Four of the synthesised compounds showed <10 uM IC50's. Chapter Three gives an account of the invention of a novel 3-component cascade synthesis of diindolylmethane compounds, three of which have demonstrated selectivity and < 10 uM activity against the LNCaP prostate cancer cell line in vitro. Derivatives of two of these. compounds in turn show enhanced selectivity and 0.5 - 2 uM activity against the LNCaP and PC3 prostate cancer cell lines. A short review of the relevant chemistry is given at the beginning of the chapter. Chapter Four furnishes full experimental details of the work carried out, together with appropriate data.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available