meso-2,3-Dimercaptosuccinic Acid Mono-N-alkylamides:  Syntheses and Biological Activity as Novelin VivoCadmium Mobilizing Agents

Abstract

Three meso-2,3-dimercaptosuccinic acid mono-N-alkylamides (meso-RNHCOCH(SH)CH(SH)-COOH, where R = CHMe2, Mi-PDMA; CH2CHMe2, Mi-BDMA; and CH2CH2CHMe2, Mi-ADMA), were prepared via a synthetic route using the sulfhydryl-protected anhydride. 2,2-Dimethyl-1,3-dithiolane-4,5-cis-dicarboxylic acid anhydride was opened up with 1 mol of corresponding amine to give the SH-protected monoamide. Subsequent deblocking of the vicinal dithiol functionality was accomplished by conversion of the dithiolane into the mercury complex followed by reaction with H2S to give the target molecule. The potential utility of these compounds in chronic cadmium intoxication was examined by evaluation of their cadmium mobilizing efficacy in vivo in cadmium-loaded female albino rats using sodium N-benzyl-D-glucamine-N-carbodithioate (BGDTC) as the standard drug. Compared to BGDTC, the new compounds were, except at the highest dosage studied, equally or more effective in decreasing retention of hepatic cadmium, while mostly less effective in decreasing renal cadmium. The greatest reductions were obtained with Mi-BDMS at 4 x 1.5 mmol/kg, where liver and kidney cadmium levels were reduced to 12% and 59% of control levels, while at the same dosage BGDTC induced a reduction to 50% and 13% of control levels. The order of the efficacy of the monoamides as hepatic cadmium mobilizing agents was found to be Mi-PDMA > Mi-BDMA > Mi-ADMA. However, the isopropyl analog, though very effective at reducing hepatic cadmium at a low dosage, was found to be more toxic than the isobutyl and isoamyl monoamides. While the new compounds were shown to be effective cadmium mobilizing agents, the specific compounds examined did not possess optimized structures in terms of the balance between effectiveness and toxicity.

On the effect of chelating agents and antioxidants on cadmium-induced organ toxicity. An overview

“…A comparative study on the effect of the chelating agents N- Mi-BDMA (meso-2,3-dimercaptosuccinic acid monoisobutylamide) and Mi-ADMA (meso-2,3dimercaptosuccinic acid monoisoamylamide) are effective in mobilizing Cd from the liver but are not that much effective in reducing the Cd concentration in the kidneys. At optimum dose Mi-BDMA reduces renal Cd concentration to 40% compared to the toxic control [46].…”

“…DMSA and DMPS reduce Cd in the kidneys of mice, exposed to Cd intoxication, but DMSA is not effective in eliminating Cd from intracellular deposits. Therefore this agent is not very suitable for the treatment of chronic Cd-intoxication [46].…”

“…DFO and monensin are most effective in the elimination of Cd in animals, exposed to acute and subactute Cd-intoxication. Both agents have been demonstrated to improve iron homeostasis and could be applied orally [46,67].…”

Mobilisation of Cadmium by meso- and racemic-2,3-Dimercaptosuccinic Acid (DMSA) in Rats

“…It effectively prevents the absorption of cadmium from the gastrointestinal tract (Jones 1991). Different esters or amides of meso-DMSA were also studied for mobilisation of aged intracellular deposits of cadmium with varying success (Jones et al 1988(Jones et al , 1992(Jones et al , 1994aSingh et al 1996b). Under these conditions most of other efficient chelators are basically carbodithioate derivatives (Jones & Cherian 1990;Singh et al 1996a).…”

Mobilisation of Cadmium by meso‐ and racemic‐2,3‐Dimercaptosuccinic Acid (DMSA) in Rats

“…Under these conditions most of other efficient chelators are basically carbodithioate derivatives (Jones & Cherian 1990; Singh et al 1996a). Different esters or amides of meso-DMSA were also studied for mobilisation of aged intracellular deposits of cadmium with varying success (Jones et al 1988(Jones et al , 1992(Jones et al , 1994aSingh et al 1996b). Recently the racemic isoform of DMSA (rac-DMSA) has been found to be more efficient than the meso-DMSA to mobilise other metals such as lead and mercury Kostial et al 1997).…”