The first chapter of this thesis introduces enzymes as inspiring catalysts,focusing on the flavin and nicotinamide cofactors. Because the catalytic activity ofnatural enzymes is limited, biomimetics have emerged as promising alternatives. Anoverview of flavin and nicotinamide mimetics published in the literature is provided.Aspects of their synthesis and properties are discussed.The second chapter gives a descriptive analysis of the existent crystalstructures of flavoenzymes available within the Protein Data Bank. The work has beenperformed with the aid of a Python script developed for this purpose by my mainsupervisor that maps the AA residues forming the binding pocket of flavin andnicotinamide cofactors. The ultimate goal of this project is to construct acomprehensive and systematic survey that can be useful in flavoenzymatic modelstudies and synthesis of flavoenzyme mimetics.Chapter 3 focuses on the design of flavin and nicotinamide mimetics with thiolgroups that can serve as building blocks for Dynamic Combinatorial Chemistry. Thefirst part describes the synthesis and characterisation of nicotinamides substituted withsimple alkyl substituents and monothiol functionalities. Attempts to make dithiolsynthetic nicotinamides are discussed. The second part of this chapter reports thesynthesis of the first cysteine-functionalised riboflavin derivative. During the attemptsto prepare dithiol isoalloxazines, alloxazine tautomers have been obtained which haveled to the first examples of dithiol alloxazines.Chapter 4 describes further attempts to synthesise dithiol isoalloxazines. Whileworking towards this goal, seven new isoalloxazines with achiral and chiralsubstituents in position N10 have been obtained and published in the literature.Optimisation of the reaction conditions has led to the synthesis of the first free dithiolisoalloxazine.Chapter 5 reports the design of the first generation of molecular rotors basedon flavins. The fixed part of the rotors is the azaisoalloxazine core, and the rotatoryunits are a series of chiral and achiral moieties. The physicochemical properties of thefour rotors are discussed. The rotors are able to perform autonomous motion and theirrotation is also driven by temperature, protonation-deprotonation andreduction-oxidation equilibria. Each rotor behaves differently under these stimuli.8Chapter 6 describes all experimental methods used to produce the work in thisthesis. These include synthetic protocols, characterisation of synthesised moleculesand analytical methods employed for this purpose.The last chapter is a general conclusion of the research reported in this thesis.Several ideas for potential future work are also suggested.
|Date of Award
|14 Sept 2022
|Dan Pantos (Supervisor) & Christopher Pudney (Supervisor)