Complexation of Copper and Iron by Biologically Relevant Sulfur- and Selenium-Containing Small Molecules
Date of Award
Doctor of Philosophy (PhD)
Julia L. Brumaghim, Committee Chair
Brian A. Powell
William T. Pennington
Andrew G. Tennyson
Misregulation of cellular copper and iron can increase labile pools of these metal ions, increasing oxidative damage and leading to neurodegeneration in Wilson's, Parkinson's, and Alzheimer's diseases. Chapter 1 of this dissertation provides an overview of the thermodynamic stability constants of Cu(II), Cu(I), Fe(II), and Fe(III) with weakly binding amino acid ligands, including sulfur- and selenium-containing amino acids and drugs such as methimazole and penicillamine. Understanding these metal-amino-acid interactions provides insight into the role of cellular amino acids as ligands for labile metals. Stability constants of Cu(II) and Fe(II) with the sulfur- and selenium-containing amino acids methionine, selenomethionine, methylcysteine, methylselenocysteine, and penicillamine are reported in Chapter 2. Potentiometric titration data and characterization by X-ray structural analysis, infrared spectroscopy, and mass spectrometry indicate that the coordination modes and stabilities of thio- and selenoether-amino acids with Cu(II) are similar to glycine and do not involve coordination of the sulfur or selenium atom. Fe(II) stability constants with these amino acids were considerably lower than those with Cu(II), indicating that Fe(II) complexes of these amino acids likely do not form under biological conditions. Fe(II) binding to the thiol penicillamine, used to treat copper overload in Wilson's disease, is significantly more stable, suggesting potential competition with Cu(II) for penicillamine binding. The thione methimazole is a redox-active, hyperthyroid drug that strongly coordinates copper. Reactions of methimazole with Cu(II) or Cu(I) and the effects of oxidation state and oxygen availability on the resulting copper-coordinated products were explored (Chapter 3). Dinuclear, polymeric, and mononuclear complexes are obtained that involve redox reactions of both copper and methimazole, some of which result from sulfur elimination from the oxidized methimazole disulfide ligand. An updated mechanism is proposed for this unusual reaction. Under air-free conditions, treating Cu(I) with methimazole disulfide results in disulfide bond cleavage to afford a copper-bound methimazole complex (Chapter 4). The analogous selenomethimazole complex forms from methimazole diselenide, and copper coordination chemistry of selenomethimazole is even more complex than that of methimazole. The remarkable diversity of copper methimazole and selenomethimazole complexes highlights the redox chemistry of metal and ligand and is highly dependent upon reaction time, solvent, and oxygen availability.
Murphy, Jaime Melissa, "Complexation of Copper and Iron by Biologically Relevant Sulfur- and Selenium-Containing Small Molecules" (2018). All Dissertations. 2201.