Date of Award

12-2014

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Legacy Department

Chemistry

Committee Member

Dr. Julia L. Brumaghim, Committee Chair

Committee Member

Dr. Jeffrey N. Anker

Committee Member

Dr. Gautam Bhattacharyya

Committee Member

Dr. William T. Pennington

Abstract

DNA damage by reactive oxygen species (ROS) is a cause of many chronic diseases. This work examines the ability of sulfur and selenium antioxidants to prevent oxidative DNA damage and the mechanisms for this activity. Although iron- and copper-generated hydroxyl radical are primary causes of damage under oxidative stress conditions, studies typically focus on ROS scavenging rather than antioxidant-metal binding as a mechanism for sulfur and selenium antioxidant behavior. Mass spectrometry studies of sulfur and selenoamino acids (Chapter 2) show that most form CuI and FeII complexes, regardless of their metal-mediated DNA damage prevention abilities. Because their electrochemical properties do not correlate to antioxidant activity, metal binding rather than ROS scavenging is the major mechanism for these sulfur and selenium antioxidants. DNA damage assays with N,N’-dimethylimazole thione (dmit) and selone (dmise) determined that both prevent CuI-mediated DNA damage (IC50 = 1550 and ~240 µM, respectively; Chapter 3). Surprisingly, dmit and dmise more effectively inhibit FeII-mediated DNA damage (IC50 = 89.1 and 3.2 µM, respectively), an ability not previously observed for this class of antioxidants. Dmise and dmit coordinate CuI and FeII and prevent DNA damage by peroxynitrite (IC50 = 171.4 and 155.2, respectively). Studies with similar thiones, selones, and their derivatives (Chapter 4) showed that these compounds are also multifunctional antioxidants, preventing DNA damage by CuI (IC50= 22-1023 µM), FeII (IC50 = 2.3-1000 µM) and peroxynitrite (IC50 = 57.4-594 µM). Many of these compounds readily undergo oxidation and reduction, and mass spectrometry studies show CuI or FeII coordination, regardless of antioxidant activity. These are the first sulfur and selenium compounds with multifunctional antioxidant activity, and the structure-activity relationships established in this work will allow development of more potent antioxidants for disease treatment and prevention. Studies in Chapter 5 focus on how metal binding alters drug properties. Clotrimazole-metal complexes kill cancer cells, yet their cytotoxic mechanisms are not understood. Similarly, studies have not examined the effects of metal coordination on the biological properties of pseudoephedrine-derived compounds. DNA damage studies with copper complexes of both compounds found that they significantly damage DNA (EC50 = 10.5-21.7 µM), likely by copper-mediated ROS generation.

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