Design of in vivo Cadmium-Mobilizing Agents: Synthesis and Properties of Monobenzyl meso-2,3-Dimercaptosuccinate

Abstract

A novel method for the synthesis of monoesters of meso-2,3-dimercaptosuccinic acid (DMSA) is presented which utilizes the reaction of the vicinal sulfhydryl-protected anhydride with the corresponding alcohol in the presence of a base. The product is then treated successively with mercuric chloride to remove the protecting group and form the mercuric complex, and hydrogen sulfide to regenerate thiol groups by removal of mercury as HgS. This strategy was exploited to synthesize monobenzyl meso-2,3-dimercaptosuccinate (MBzDMS), C6H5CH2O(O)CCH(SH)CH(SH)C(O)OH, and demonstrates a feasible synthesis of monoesters difficult to obtain by direct esterification, via the use of the reactive anhydride. The resultant compound was found to be an effective cadminum-mobilizing agent when used with cadmium-exposed rats or mice and when administered by any one of several routes (ip, iv, po). This monobenzyl ester (MBzDMS) of DMSA was found to be somewhat less effective than the corresponding monoisoamyl ester (Mi-ADMS) in mobilizing cadmium from such cadmium deposits. The ability of MBzDMS to mobilize cadmium into the urine is significantly decreased by the coadministration of p-aminobenzoic acid, in support of the hypothesis that MBzDMS enters renal cells via an anion transport system. An analysis of the structural features of vicinal dithiols examined as antagonists for chronic cadmium intoxication allows a hypothesis to be formulated indicating essential features required for the design of effective new cadmium antagonists of this type.

Reactions of the Zn Proteome with Cd2+ and Other Xenobiotics: Trafficking and Toxicity

“…14 To a lesser extent, Cd 2+ and Pb 2+ also prefer thiolate ligand coordination. 15,16 However, these restrictions hardly limit the number of possible binding sites. Thiol groups are found in many enzyme active sites, as ligands of protein-bound metal ions, among amino acid side chains on the exterior of protein structures, and as part of the glutathione tripeptide that is present in cells at 1−10 mM concentration.…”

Combined Early Treatment with Chelating Agents DMSA and CaDTPA in Acute Oral Cadmium Exposure

“…DMSA, an analogue of BAL (2,3-dimercaptopropanole) is much less toxic and has the additional advantage that it can be administered orally. The complex formed with cadmium is ionic and is excreted via the kidney (Jones et al 1994). Another chelator belonging to poliaminopolicarboxilate group of chelators is the commonly available chelating agent calcium trisodium diethylenetriaminepentaacetate (CaDTPA).…”

“…It used to be applied in persons contaminated with plutonium or americium. Since CaDTPA is very slightly absorbed following oral administration, it is usually given by injection (Cantilena & Klaassen 1981; Klaassen et al 1984; Andersen 1989b; Jones & Cherian 1990; Jones et al 1994). It very efficiently reduces oral cadmium toxicity provided the treatment is started very soon after the ingestion of cadmium compounds (Andersen 1999).…”

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).…”