Insights into Aminofluorination Strategies and Sphingosine Analogue Synthesis towards the Development of Selective SphK2 Inhibitors

Identifier:  TDX:4433

Handle: https://hdl.handle.net/20.500.11797/TDX4433

Authors:  Granell Fort, Albert

Abstract:
Investigating the synthesis of sphingosine analogues as potential inhibitors of enzyme Sphingosine Kinase (SphK), this thesis focuses on two main areas: 1) the synthesis of sphingosine analogues for cancer therapy and 2) the study of aminofluorination of allyl carbamates using hypervalent iodine reagents. Chapter 3 explores attempts at the enantioselective preparation of sphingosine analogues with promising inhibition activity against SphK2. The research investigates the interaction between these analogues and the active site of SphK1/2 through molecular dockings and homology modelling. Cell viability assays reveal negligible cytotoxicity of one of the synthesized analogues. Chapter 4 delves into the study of aminofluorination using hypervalent iodine reagents applied to allyl carbamates, aiming to develop a methodology for obtaining β-fluoroamines towards the synthesis of C-3 fluorinated sphingosine analogues. The effects of carbamate substitution and acidity, as well as double bond configuration, on reaction efficiency and stereoselectivity are explored. Computational calculations, kinetic studies and Hammett competition plots are used elucidate the mechanism of the reaction, shedding light on the decisive events for selectivity.