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.