Oxidation of a Dimethylthiourea Metabolite by Iodine and Acidified Iodate: N,N‘-Dimethylaminoiminomethanesulfinic Acid ()

Abstract

The two major metabolites after S-oxygenation of dimethylthiourea (dimethylaminoiminomethane sulfinic acid, DMAIMSA, and dimethylaminoiminomethane sulfonic acid, DMAIMSOA) were synthesized and tested for their reactivities in the presence of mild oxidants, aqueous iodine and acidic iodate. The stoichiometry of the iodate-DMAIMSA reaction is 2IO3- + 3NHCH3(=NCH3)CSO2H + 3H2O --> 3SO4(2-) + 2I- + 3CO(NHCH3)2 + 6H+ (A). The reaction commences with immediate formation of aqueous iodine, which is produced from the reaction between the iodide product of stoichiometry (A) and reactant iodate. The instant accumulation of aqueous iodine is due to the very slow reaction of iodine with both DMAIMSA and DMAIMSOA. In excess iodate over that required for stoichiometry (A), the stoichiometry of the reaction is 4IO3- + 5NHCH3(=NCH3)CSO2H + 3H2O --> 5SO4(2-) + 2I2 + 5CO(NHCH3)2 + 6H+ (B). Even though excess DMAIMSA solutions do not afford iodine, the initial rapid formation of iodine is still observed, which reaches a peak and then decays to conform to stoichiometry (A). The maximum transient iodine concentrations obtained are directly proportional to the acid concentrations because acid catalyzes formation of iodine and retards reactions that consume iodine. The zwitterionic forms of DMAIMSA and DMAIMSOA are very stable in acid, and DMAIMSOA, especially, is very inert and unreactive in low pH environments. The predominant pathway for the oxidation of DMAIMSOA is through an initial hydrolysis reaction to yield bisulfite and dimethylurea, while the oxidation of DMAIMSA proceeds through DMAIMSOA as well as through an early heterolytic cleavage of the C-S bond to produce a highly reducing sulfoxylate species, SO2(2-), which is later rapidly oxidized to sulfate. In aerobic conditions, the sulfoxylate species reacts with molecular oxygen to produce superoxide anion radical, which in turn will form hydrogen peroxide and hydroxyl radicals which will bring with them inadvertent genotoxicity.