Selective incorporation of the C-F bond as a conformational tool in quadruplex DNA ligand design

Abstract

Chapter 1 provides a general introduction to organofluorine chemistry and focuses on recent developments in fluorination techniques. It also details how the C–F bond influences conformational and physiochemical properties of organic molecules. Chapter 2 highlights the biological role of the telomere, telomerase and quadruplex DNA in cells. It discusses the inhibition of telomerase with small molecules that stabilise quadruplex DNA as a treatment for cancer. An overview of the development of structurally related telomerase inhibitors and recent X-ray crystallographic structural data with BSU6039 and BRACO-19 telomeric DNA is presented. Chapter 3 discusses the synthesis of fluorinated BSU6039 analogues for the investigation of the conformational effects of fluorine in 5-membered rings and its influence on binding with quadruplex DNA. These compounds have been successfully co-crystallised with telomeric DNA and their relative stabilisation of telomeric DNA has been assessed. The latter half of this chapter focuses on the co-crystal structures between (S,S)- and (R,R)-144 with Oxytricha nova telomeric DNA, discussing the key differences between the two stereoisomers. Chapter 4 details the synthesis of fluorinated BRACO-19 analogues. The syntheses of such fluorinated analogues were achieved through a base mediated coupling between 3,6-diaminoacridone and an α-fluorinated-β-amino ester. The α-fluorinated-β-amino ester was synthesised through a deoxyfluorination-mediated approach, using the stereochemistry of natural amino acids. Chapter 5 describes the stereo- and regio- selectivity of deoxyfluorination reactions with dipeptides bearing the β-amino alcohol functionality. Understanding this selectivity enabled the development of a method towards α-fluorination of tertiary amides. The application of this fluorination method with an orthogonally protected tertiary amide is described.