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Title: Synthesis and evaluation of novel PI3-K-Akt-mTOR modulators
Author: Gunn, Richard Martin
ISNI:       0000 0004 2706 2711
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2010
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The phosphoinositide 3-kinase / Akt / mammalian target of rapamycin (PI3-K-AktmTOR) signalling pathway is a regulator of critical cellular functions including apoptosis, metabolism and survival. Its deregulation is involved in numerous human diseases. This thesis describes the synthesis and biological evaluation of a series of analogues of the PI3-K-Akt-mTOR inhibitor E1, a homo-dimeric diarylmethane. Several structurally diverse hetero-dimeric E1 derivatives were discovered that inhibited PI3-K-Akt-mTOR signalling in human cancer cells. Chapter 1 provides an overview of the PI3-K-Akt-mTOR signalling pathway and its biological significance. Chapter 2 discusses the use of small molecules for the investigation of PI3-K-Akt-mTOR signalling, with examples given by structural class. It concludes with a profile of lead compound E1. Chapter 3 outlines the proposed approach to analogue synthesis by the coupling of functionalised building blocks, and describes the development of building block compounds via the orthofunctionalisation of phenol derivatives. Chapter 4 describes efforts towards the derivatisation of E1 with a linker group in order to allow the conjugation of biotin for affinity chromatography, or the incorporation of other groups useful for biological characterisation. In Chapter 5, the coupling of building blocks via C-C, C-O, C-N and N-S bond-forming reactions to generate homo- and hetero-dimeric E1 derivatives is discussed. Several of these compounds were capable of inducing cellular Akt inhibition. Chapter 6 focuses on the synthesis of hetero-dimeric analogues based on these new lead compounds. The biological evaluation of E1 derivatives in a cellular assay is described in Chapter 7. Finally, detailed experimental procedures are described in Chapter 8.
Supervisor: Hailes, Helen ; Woscholski, Rudiger Sponsor: EPSRC ; DAAD
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral