Sulfur mustard (SM; bis 2-(chloroethyl) sulfide; mustard gas) has been used in chemical warfare since World War I, and is well known for its acute toxicity in skin, cornea and bronchial epithelium. It has also been implicated as a lung carcinogen after chronic, low-level exposure. SM has been shown to be highly mutagenic, due to formation of DNA inter-strand crosslinks. Due in part to ease of synthesis, there is renewed interest in both nitrogen and sulfur mustard as potential terrorist weapons against civilian populations. Since SM reacts as a strong electrophile, we reasoned that low molecular weight nucleophiles, previously identified as effective scavengers of other electrophilic carcinogens, would likely react with SM, and thus might be useful as potential protective agents. Accordingly, we have determined rate constants for the reaction of four purine derivatives that contain nucleophilic thiol moieties with 2-(chloroethyl) methyl sulfide (CEMS) and 2-(chloroethyl) ethyl sulfide (CEES), half-mustard analogs of SM. Three of these compounds, 2,6-dithiopurine, 2,6-dithiouric acid and 9-methyl-6-mercaptopurine, exhibit facile reaction with both CEMS and CEES. The rate constants for these reactions at pH 7.6 and 23°C range from 48.1 to 78.5 L/mol-sec, three to four-fold faster than the previously determined rates of reaction of the same thiopurines with the well-studied carcinogen 7r,8t-dihydroxy-9,10t-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene. The temperature-dependence of these rate constants indicates that these reactions are SN1, as expected from previous studies of the hydrolysis of SM and CEMS. At high concentrations of reactants, adducts derived from the addition of two, three and four half mustard molecules to each thiopurine molecule can readily be detected by mass spectrometry. At near neutral pH, these thiopurines are much better nucleophilic scavengers of mustard electrophiles than other low molecular weight thiols such as N-acetyl cysteine and glutathione, and therefore appear to have better potential as chemoprotectants.
99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA