Selectively fluorinated compounds as bioactives and biomolecular probes

Abstract

Fluorine’s role in medicinal chemistry and biochemistry cannot be overstated. Its small atomic radius and high electronegativity make fluorine a versatile tool for the design of novel drugs and biomolecular probes.

In Chapter 1 a history of fluorine chemistry is presented, followed by a general discussion of the dominant interactions associated with organofluorine compounds. Fluorine’s role in medicinal chemistry, specifically its use in antibiotics is explored, which is followed by a deeper look into the drug resistant bacterium Mycobacterium abscessus. Both the all syn pentafluoro cyclohexane and binding methods of molecules to DNA will also be examined, foreshadowing the work done in the following chapters.

Chapter 2 details the design, synthesis, and testing of a collection of novel fluorinated β-lactam lactamase inhibitors and antibiotics. Synthesised β-lactams are assayed against an array of drug resistant bacteria, predominantly M. abscessus strains. The mechanism of action is also investigated through chemical hydrolysis of the β-lactam ring, which is studied through multiple NMR time courses.

In Chapter 3 the interaction between an all syn pentafluoro cyclohexane “Janus face” molecule and both double strand and single strand DNA is investigated. Using biophysical methods centred around Förster resonance energy transfer (FRET), an interaction between DNA and the Janus face motif is described. Chapter 3 also details the synthesis of multiple pentafluoro cyclohexane “building blocks” and biological probes.

Chapter 4 reports the synthesis of a radiotracer which constitutes a pentafluoro cyclohexane motif. The enzymatic radiolabelling via the fluorinase enzyme is reported, and evidence of a radioactive pentafluoro cyclohexane probe is reported. Synthesis of additional biomolecular probes for use in a medicinal setting is also described.

Finally, Chapter 5 explores the synthesis of novel A2A receptor agonists which posses a pentafluoro cyclohexane motif. The agonists are subsequently assayed in a radiotracer displacement experiment which showcases the relatively high affinity of the agonists for the human A₂A receptor.