Date of Award

5-2011

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Legacy Department

Chemistry

Advisor

Brumaghim, Julia L

Committee Member

Bhattacharyya , Gautam

Committee Member

Newby , Meredith

Committee Member

Hwu , Shiou-Jyh

Abstract

In Fenton-like reactions, Cu+ localized on DNA reduces hydrogen peroxide to form hydroxyl radical (*OH), resulting in oxidative DNA damage. This DNA damage causes mutation and cell death, which can lead to diseases such as cancer, Alzheimer's, and arteriosclerosis. Sulfur and selenium antioxidants have been investigated for the prevention and treatment of these diseases, and studies have shown that sulfur- and selenium-containing antioxidants prevent DNA damage from copper-generated hydroxyl radical and that metal coordination is required for the observed antioxidant activity.
To determine how copper coordination results in DNA damage inhibition, Cu+ complexes with selone and thione ligands were synthesized with the aim of studying their electrochemistry and reactivity with H2O2. Tris(pyrazolyl)methane and -borate ligands are used to synthesize the target metal complexes, since they mimic metal coordination environments in biological systems. N,N'-1,3-dimethyl-imidazole thione (dmit), and selone (dmise) ligands are used since they resemble ergothioneine and selenoneine, sulfur and selenium-containing antioxidants naturally found in plants and animals. Selone coordination to Cu+ significantly stabilizes Cu2+ more effectively than thione coordination by an average of 224 mV. The copper-selone complexes of the formula [TpmRCu(dmise)]+ and Tp*Cu(dmise) (TpmR = tris(pyrazolyl)methane, R = H; Tpm, R = Me; Tpm*, R = iPr; TpmiPr; Tp* = tris(1,3-dimethylpyrazolyl)borate) have potentials from -283 mV to -390 mV, while the analogous thione complexes ([TpmRCu(dmit)]+ and Tp*Cu(dmit)) have potentials ranging from 70 mV to -232 mV. If similar Cu-Se complexes are formed in vivo, these potentials may be low enough to inhibit Cu2+ reduction by NADH and prevent copper redox cycling.
The reactivity of dmise, dmit, and their tris(3,5-dimethylpyrazolyl)methane copper complexes [Tpm*Cu(L) (L = dmise or dmit) with H2O2 was explored. Dmise and dmit are both reactive towards H2O2 and may be effective scavengers of H2O2. Treatment of [Tpm*Cu(dmise/dmit)]+ with H2O2 showed sacrificial oxidation of the chalcogenone without oxidation of the Cu+ metal center, and if similar copper-selenium or -sulfur complexes form in vivo, these complexes may scavenge H2O2 and inhibit copper-mediated oxidative damage.
A comparative coordination chemistry and density functional theory study of selone and thione with cuprous halides was also performed, and the resulting complexes have varied geometries and stochiometries depending on the type of halide and chalcogenone ligand used, intramolecular π-π interactions, and degree of short contact interactions between X-H (X = I, Br, Cl, Se or S) atoms in the solid state structures. Cu+ complexes of the bidentate thio- and seleno-imidazolyl ligands bis(thioimidazolyl)methane, bis(selenoimidazolyl)methane, bis(thioimidazolyl)ethane, and bis(selenoimidazolyl)ethane were synthesized, and these complexes preferentially formed dinuclear, three- and four-coordinate Cu+ complexes. The Cu2+/+ reduction potentials of these copper complexes with bidentate chalcogenone ligands vary within a range of 471 mV, a difference that would have significant effects in redox-mediated reactions. The results presented give more insight on the antioxidant activity of selone and thione compounds in the prevention of copper-mediated oxidative damage. These results also reveal the diverse coordination chemistry of Cu+ with selone and thione and elucidates the effects of this coordination on Cu2+/+ reduction potentials.

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