Synthesis and Application of Succimer

General description

2,3-Dimercaptosuccinic acid (abbreviation: DMSA), alias 2,3-dimercaptosuccinic acid, is an organic sulfur compound, which is a white crystalline powder at room temperature. Because it contains two sulfhydryl groups in the molecule, it has the unique odor of sulfhydryl compounds. Both dimercaptosuccinic acid and its sodium salt can be used as antidote for heavy metal poisoning by oral or injection. Dimercaptosuccinic acid has two diastereomers, one is a meso form and the other is a racemate. The meso body can be used as a chelating agent, and its sodium salt is commonly used.

Fig. 1 The structure of Succimer.

Synthetic routes

Fig. 2 The synthetic method 1 of Succimer.

Isolate the solid complexes of trivalent lanthanide complexes with meso-2,3-Dimercaptosuccinic Acid, furan-2-carboxylic acid, meso-2,3-dimercaptosuccinic acid and sarcosine from the mixture of equimolar solutions of metal nitrates and ligands. Adjust the pH of the mixture to 7 by adding dilute solution of KOH. Reflux the mixture in ethanol (15-20 ml) for 3-4 hours on a steam bath. The clear solution gives a solid mass on cooling, filter through G4 glass crucible and wash several times with the mixture of doubly distilled water and alcohol. Recrystallise it to obtain pure crystal and dry at 60 ° -70 °C [1].

Fig. 3 The synthetic method 2 of Succimer.

In a light-blocked three neck round bottom flask 60 mL of ethanol was deoxygenated by bubbling N₂ gas. Silver nitrate (86.6 mg, 0.51 mmol) and nickel nitrate hexahydrate (26.2 mg, 0.09 mmol) were added and allowed to dissolve. The flask was sealed with rubber septa, purged with nitrogen, and cooled to 0 °C in an ice bath. The flask was briefly opened to add dimercaptosuccinic acid (108.0 mg, 0.57 mmol), resealed and purged again. The solution was stirred slowly under gentle nitrogen flow for the next four hours. A solution of sodium borohydride (5 mL, 0.246 mM in EtOH) was prepared and inject ed with vigorous stirring. The solution was left overnight over which time the temperature was allowed to rise to ambient conditions. The product suspension was centrifuged out of the ethanol (9000 RPM, 10 minutes) and the solid was washed with additional ethanol followed by methanol. The solid was dried under gentle nitrogen flow and then dissolved in deionized H₂O. This solution was centrifuged to remove insoluble side products and the supernatant was combined with ethanol, resulting in the precipitation of the cluster. The suspension was centrifuged and the solid was dried under gentle nitrogen flow. Ag₄Ni₂(DMSA)₄. m/z: 422.0829; Assigned Formula (mass and isotope distribution match): Ag₄Ni₂(C₄H₄O₄S₂)₄ [2].

Application

Effects on growth and development of preschool children with moderate blood lead

Although many studies have demonstrated the efficacy of succimer chelation in reducing blood and brain lead levels, the relative efficacy of the drug in the two tissues is less well understood. This issue is important because blood lead levels after chelation are used clinically to estimate reductions in the brain, the most critical organ in considering lead-induced neurotoxicity. The present study was designed to further investigate this issue, using multiple chelation regimens. Long-Evans rats were exposed to one of three lead exposure regimens from birth until postnatal day 40, followed by treatment with succimer (one or two 3-week regimens) or vehicle. The results indicated that one succimer regimen was significantly superior to vehicle treatment in lowering lead levels in both blood and brain across the entire 8-week follow-up period. Similarly, a second succimer regimen offered significant additional benefit relative to one regimen for both blood and brain across the 4-week follow-up period. However, several findings revealed that succimer-induced reductions in brain lead lagged behind reductions in blood lead and were generally smaller in magnitude. Furthermore, a rebound was detected in blood, but not brain, lead levels after both succimer regimens. Given the results of this study, we urge caution in using blood lead as a surrogate for brain lead levels, particularly during and immediately after chelation treatment when reductions in blood lead levels overestimate reductions in brain lead levels. The present results suggest that, in clinical use, succimer treatment may need to extend beyond the point at which blood lead levels have dropped to an "acceptable" target value in order to effectively reduce brain lead levels and minimize neurotoxicity [3].

Growth deficits associated with lead exposure might be ameliorated by chelation. We examined the effect of succimer on growth in 780 children 12-33 months old who had blood lead levels of 20-44 mug/dL and were randomized to receive up to three 26-day courses of succimer or placebo in a multicenter, double-blind trial. The difference in changes in weight and height between succimer and placebo groups at 1-34 months was calculated by fitting cubic splines. The difference in height change in children on succimer compared with placebo was -0.27 cm [95% confidence interval (95% CI), -0.42 to -0.11] from baseline to 9 months, when 99% of children had completed treatment, and -0.43 cm (95% CI, -0.77 to -0.09) during 34 months of follow-up. Similar differences in weight gain were not statistically significant. Although succimer lowers blood lead in moderately lead-poisoned children, it does not have a beneficial effect on growth and may have an adverse effect [4].

Effects on auditory function of rhesus monkeys

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