The extension of drug delivery potential using Tiara[n]uril

Abstract

Tiara[n]uril is a new class of glycoluril-based macrocyclic hosts, characterized by the presence of a positively charged cavity comprising of glycoluril moieties linked to two pyrazolium groups. Being a recently discovered macrocycle, only a few Tu[n] derivatives have been synthesized and reported. However, these Tu[n]s are restricted to homologues no larger than Tu[3], which indicates synthetic opportunities towards the attainment of higher homologues through variation of substitutions on the glycoluril moieties. Presented in this thesis is the synthesis of new members of Tu[n] family - tetrahydrothiophenetiara[n]uril (THTnTu[n]). A reaction sequence was designed to achieve homologues of Tu[n] (n>3) through equatorial introduction of THT functionality. This synthetic route provided access to two THT functionalized Tu[n]s - THT3Tu[3]2+ and THT4Tu[4]2+, where the later represents the first example of higher homologue in Tu[n] family. The structural properties of purified THT3Tu[3]2+ and THT4Tu[4]2+ were fully elucidated using different techniques. Furthermore, attempts to bias the product distribution towards THT4Tu[4]2+ was illustrated through the use of different acids, which indicated the influence of an anionic template in attaining improved higher homologue (n=4) proportion. The second objective of the work was to develop an understanding of the binding capabilities of methyl and THT substituted Tu[n]s to establish their potential for functional applications. The binding association of Me10Tu[3]2+, THT3Tu[3]2+ and THT4Tu[4]2+ were explored with a selection of guests suitable for the testing of a preliminary understanding. The association towards an inorganic (HCl), and organic guest (L-glutamine) was demonstrated through an increase in pKa for HCl and changes in CD and fluorescence outcome for the amino acid. In addition, the cavity encapsulating feature of THT4Tu[4]2+ was established with the guests - dioxane and d8-dioxane. The binding constants were determined using comparative binding and d8-dioxane was found to bind more strongly than dioxane. Furthermore, Me10Tu[3]2+ was investigated for it’s possible effectiveness as a solubilizing excipient for the poorly soluble oral drugs. The preliminary results indicated formation of association complexes as reflected by changes in their solubilities at two pH conditions - 3.5 and 7.4. These solubility results suggests that Me10Tu[3]2+ or related Tu[n]s may have potential in future drug delivery applications.