Metal-templated synthesis of forward and reverse Fe(III)- or Ga(III)-desferrioxamine E and ringexpanded macrocycles

Abstract

Desferrioxamine E (DFOE) is a macrocyclic trihydroxamic acid-based siderophore that is produced by Streptomyces species for Fe acquisition. Macrocyclic molecules of this class have applications in biomedicine and imaging. This study aimed to synthesize metal-loaded DFOE and analogs using a metal-templated synthesis (MTS) approach from the cognate monomeric fragments. Chapter 2 described the synthesis of forward and retro hydroxamic acids as characterized by NMR, LC-MS and ESI-MS. These hydroxamic acids were subjected to metal templation and cyclization chemistry to synthesize metal-loaded DFOE and analogs. Chapter 3 and 4 described the synthesis of metal-loaded DFOE and ring-expanded macrocyclic analogs as determined by LC-MS and ESI-MS. The LC-MS results suggested that the metal-loaded retro analogs were more lipophilic than the forward isomers. This provides one rational for the predominance in nature of forward hydroxamic acids as effective Fe(III) solubilization agents. Chapter 5 described the synthesis of biotinylated desferrioxamine B (DFOB) using a new form of solid phase organic phase (SPOS) and solution phase chemistry as determined by NMR, LC-MS and ESI-MS. The thesis in total describes new synthetic methodologies to generate macrocyclic siderophore derivatives, and other siderophore adducts.