Development and Application of Therapeutically Focused Synthetic Anion Transporters.

Abstract

This thesis details the development of novel synthetic anion receptors and transporters, with a focus on augmenting their cellular effects to further advance their therapeutic application.

Chapter 2 describes the synthesis, anion binding, transport, selectivity, and cellular activity of a series of furazan-centred receptors. The novel five-membered ring architecture of the series led to an interesting anti-anti conformation driven by a network of internal hydrogen bonds. The receptors perturbed pH gradients in liposomal fluorescence-based assays and a wide range of cytotoxicities were exhibited against cancerous and normal cell lines.

Chapter 3 details the incorporation of several fluorophores into an ortho¬-phenylene scaffold to further elucidate the cellular effects of this highly potent central scaffold motif. Improved anion binding and remarkable transport abilities were exhibited by a number of novel compounds. Their cellular accumulation was examined using live cell confocal microscopy, and the cell viability of the library was examined against a cancer cell line. Each fluorophore showed distinct advantages in specific areas of application, revealing important structural considerations in the adaptation of anionophoric scaffolds.

Finally, Chapter 4 presents the first example of anionophores that accumulate in organelles previously unexplored in the context of anion transmembrane transport. Organelle targeting motifs were incorporated into a naphthalimide scaffold to afford a library of fluorescent anion receptors capable of anion binding and transmembrane transport at micromolar concentrations. Fluorescence microscopy in live cells confirmed their concentrated accumulation in specific membrane-bound organelles. Moreover, perturbation of the subcellular localisation was found to enhance both the cytotoxicity and apoptotic cell death in cancerous cells, providing an alternative approach in the design of therapeutically focused synthetic anionophores.