Non-symmetric ethylenediamine based chelators for copper and manganese

<p dir="ltr">This thesis centres on the design of novel ethylenediamine based <i>C</i>₁-non-symmetric ligands for the complexation of Cu(II) and Mn(II). The complexation behaviour, therapeutic potential and the catalytic applicability in A3 coupling reactions of the designed chelators and complexes were examined.</p><p dir="ltr"><b>Chapter</b><b> </b><b>2</b><b> </b>presents a new synthetic methodology for the synthesis of <i>C</i>_<em>1</em>-salan ligands endowed with (N-H) backbones. 15 examples of novel, <i>C</i>_<em>1</em>-salans with N-H backbones are reported and their complexation behaviour with Cu(II) was investigated.</p><p dir="ltr"><b>Chapter</b><b> </b><b>3</b><b> </b>utilises the synthesis disclosed in the previous chapter and presents the rational design of a tunable Cu(II) chelating scaffold, 2-(((2-((pyridin-2-ylmethyl)amino)ethyl)amino)methyl)phenol, <b>Salpyran</b>. This tetradentate ligand has an extremely high affinity for Cu compared to clioquinol (pCu7.4 = 10.65 vs 5.91), and exhibits excellent selectivity for Cu(II) over Zn(II) in aqueous media. Its action as an antioxidant was tested in tau and human prion protein assays, which reveal that <b>Salpyran</b><b> </b>prevents the formation of reactive oxygen species from the binary Cu(II)/H2O2 system, demonstrating its potential use as a therapeutic small molecule metal chelator.</p><p dir="ltr"><b>Chapter</b><b> </b><b>4</b><b> </b>utilises a ‘repurposing’ strategy for the rapid identification of ligands capable of attenuating Mn(II) neurotoxicity in <i>slc39a14</i>^{<em>U801</em>}<i> </i>loss-of-function zebrafish, a known model of Mn overload. The efficacy of four chelators that have found use as constituents of Mn(II)-based contrast agents (CAs), <i>N</i>-picolyl-<i>N,N′,N</i>′-<i>trans</i>-1,2-cyclohexylenediaminetriacetic acid (<b>PyC3A</b>) and ethylenediaminetetraacetic acid - benzothiazole aniline (<b>EDTA-BTA</b>) and their methylester derivatives <b>Me</b>_{<strong>3</strong>}<b>PyC3A</b><b> </b>and <b>Me</b>_{<strong>4</strong>}<b>EDTA-BTA</b><b> </b>on the removal of Mn in vivo were investigated. Both ligands PyC3A and <b>Me</b><b>3</b><b>PyC3A</b><b> </b>were effective in mobilising manganese from tissue stores and improving zebrafish locomotor activity.</p><p dir="ltr"><b>Chapter</b><b> </b><b>5</b><b> </b>reports the synthesis and characterisation a new dimeric Cu(II) complex, [Cu(II)₂L₂(µ₂-Cl)Cl] (<b>5.1</b>), built from an non-symmetric tridentate ligand (2-(((2-aminocyclohexyl)imino)methyl)-4,6-di-tert-butylphenol) and chloride anions. The addition of phenylacetylene into a dichloromethane solution of <b>5.1</b><b> </b>in leads to the formation of a transient radical species. A systematic investigation revealed this unusual C-H activation method is applicable for the efficient synthesis of propargylamines, without additives, within 16 hours, at low loadings and in non-coordinating solvents. The scope and limitations of this novel protocol were examined.</p>