Research in the Brumaghim group aims to understand how metal ions form radical species that damage DNA, and how antioxidants prevent this damage. Studying DNA damage inhibition by antioxidants may lead to treatments for cancer and other diseases.

Antioxidants prevent DNA damage
In cells, Fe²⁺ and Cu⁺ react with hydrogen peroxide (H₂O₂) to form hydroxyl radical (^•OH). Reactive hydroxyl radical then oxidizes and damages DNA. This oxidative DNA damage and oxidative stress is an underlying cause of many diseases, including neurodegenerative and cardiovascular diseases, and cancer. Antioxidants prevent hydroxyl radical from damaging DNA and other biomolecules, and are therefore of interest to treat and prevent diseases caused by oxidative stress.

Undamaged DNA is separated from damaged (nicked and linear) DNA using gel electrophoresis. Adding an antioxidant prevents DNA damage from metal-generated ^•OH. We quantify the amount of DNA damage inhibition seen in the gels and directly compare the effectiveness of different antioxidants.

We discovered that sulfur, selenium and polyphenol antioxidants prevent metal-mediated DNA damage through metal coordination. Currently we are developing structure-activity relationships for prevention of DNA damage by each of these classes of antioxidants. Understanding this novel metal-binding mechanism of antioxidant activity will aid the design of more potent antioxidant compounds. We are also currently investigating the interactions of antioxidants and metal ions with DNA.

Biological coordination chemistry
Since metal coordination by selenium and sulfur is a factor in antioxidant activity, we are interested in synthesizing metal-selenolate and -thiolate complexes. With these complexes, we will study the effects of M-Se or M-S coordination on Fe^2+/3+ or Cu^+/2+ redox potentials and reactivity with H₂O₂. Results from these experiments will allow us to determine mechanisms for the antioxidant activity of selenium and sulfur compounds. We are also interested in synthesis and structural characterization of iron polyphenol complexes.

To synthesize our target selenolate or thiolate compounds, we use Tp* and Tpm* (tris(3,5- dimethylpyrazolyl)borate and –methane, respectively) ligands as well as other nitrogen-donor ligands. These starting complexes have exchangeable acetonitrile ligands: LFe(CH₃CN)₃]ⁿ⁺ (L = Tp*, n=1; Tpm*, n=2). We are currently interested in synthesizing new ligands as well as synthesizing and characterizing our target complexes by NMR, X-ray crystallography, and cyclic voltammetry.

How do antioxidants promote cell survival?
Because we found that antioxidants prevent DNA damage in vitro by metal coordination, we are also interested in testing antioxidant ability to prevent cell death under oxidative stress. When cells (both bacterial and mammalian) are exposed to H₂O₂, many die due to the DNA damage from metal-generated hydroxyl radical.