REU Project 8—Reaction of halogenated hydrocarbons with cysteine derivatives and DNA bases—Dr. Kevin Williams, Chemistry Department
Halogenated hydrocarbons have been found to result in toxicity and/or tumor formation both in laboratory animals and in humans. Dihalogenated alkanes such as 1,2-dibromoethane (ethlylene dibromide) may be activated by glutathione or cysteine-containing proteins and may form a variety of DNA adducts. We hypothesize that other halogenated hydrocarbons might analogously be activated to reactive forms as a result of interaction with cysteine-containing peptides and/or proteins. We will study the interaction of halogenated hydrocarbons cysteine in both the absence and presence of DNA nucleotides. Previously, we have studied the reactions of cysteine, N-acetylcysteine, and cysteamine with 1,2-dibromoethane. In aqueous solution, elevated pH (~10) leads to significant reaction of the thiolate forms of the cysteine analogs via SN2 displacement of the bromides. Depending on the concentrations and the cysteine analog used, a variety of products are possible for reaction with 1,2-dibromoethane. Some of these products were identical to those seen with 2-bromoethanol, indicating a hydroxyethyl adduct had formed, presumably via interaction of water with an episulfonium ion. Notably, the episulfonium ion is thought to be the electrophilic form that can react with DNA bases. We will conduct further experiments in which DNA bases and short oligonucleotides are included in a reaction with cysteine derivatives and 1,2-dibromoethane at elevated pH. We will also expand our list of halogenated hydrocarbons to include 1,3-dibromopropane, 1,2-dibromopropane, 1,1,dibromoethane, 1,1,2-tribromoethane, and 1,2,3-tribromopropane. The adducts will be characterized by 1H and 13C NMR spectroscopy and mass spectrometry. A combination of WKU undergraduate students and REU students will participate in the research related to this project.
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