Improved Access to New Hydroxamic Acid Macrocycles and Linear Analogues

Abstract

The hydroxamic acid (HXA) functional group is a class of organic acid that forms stable complexes with a range of metal ions. The HXA group has been useful in therapeutic areas, such as iron chelation therapy and radiometal-immunological PET imaging. Multimeric HXA-containing compounds can adopt either macrocyclic or linear structural architectures, as comprised from endo-HXA monomeric subunits. Obtaining these endo-HXA monomers synthetically is difficult, due to low yields and inefficient reaction times. This creates issues when synthesising macrocyclic or linear products from these subunits and inhibits the ability to study these compounds in a therapeutic setting. One aim of this thesis was to revise the synthesis of the endo-HXA monomer. Subsequent to this, the endo-HXA monomers were deployed to create macrocyclic compounds using synthetic techniques, such as metal-templated synthesis (MTS) and metal-assisted ring closure (MARC). Linear constructs were produced using amide-coupling chemistry to graft an endo-HXA monomer onto the native HXA-containing desferrioxamine B (DFOB). This thesis improved the yield and efficiency of accessing endo-HXA monomers using a tailored protecting group strategy. Furthermore, endo-HXA monomer analogues were produced, which were used to create structural variation in macrocyclic and linear compounds. The endo-HXA monomers were used in an MTS approach to generate dimeric HXA macrocycles. This technique yielded analytical quantities of material. Access to these constructs was improved upon by using the MARC synthetic technique, which required the formation of one rather than two amide bonds. Linear constructs were created by amide coupling a variety of endo-HXA monomers to DFOB. These ligands could be useful in 89Zr immunological PET imaging. This thesis describes the improved synthesis of endo-HXA monomers that allowed the creation of unique macrocyclic and linear architectures that could be useful in a therapeutic setting.