Stereoisomeric Selectivity of 2,3-Dimercaptosuccinic Acids in Chelation Therapy for Lead Poisoning

Abstract

The formation constants of lead chelates of the stereoisomers of 2,3-dimercaptosuccinic acid (DMSA) were determined from potentiometric titrations in the presence of the competing ligand, EDTA. The lead chelates formed at pH 7.4 with the stereoisomers of DMSA are the monomeric complexes PbL and HPbL. Formation of PbL and HPbL at pH 7.4 is independent of total concentrations of lead and DMSA present, and so is the concentration ratio of PbL:HPbL. Lead is completely chelated at pH 7.4 when the total concentration of ligand is equal to or greater than the total concentration of lead present. Lead tends to bind to a greater extent with rac- than with meso-DMSA, and the relative extent increases with an increase in the concentration ratio of ligand to lead and finally reaches a constant value of 45. The binding sites in the chelates, PbL, of the stereoisomers of DMSA are the two thiolate groups and one carboxylate group. rac-DMSA also forms a dimeric complex Pb2L2 in which both carboxylate groups of the ligands participate in binding with lead ions. The formation constants of the lead chelates of rac-DMSA were invariably found to be larger than those of the corresponding of meso-DMSA chelates, because in all the lead chelates of the stereoisomers of DMSA formed in solution, rac-DMSA existed in staggered anti conformations, whereas meso-DMSA preferred a staggered gauche conformation with respect to carboxylate groups in the ligands. The potential of using ZnL2 of rac-DMSA as a therapeutical lead chelator was assessed by considering its lead-mobilizing ability and its ability to deplete endogenous zinc; on this basis it is predicted that ZnL2 of rac-DMSA is a better chelator than meso-DMSA for the treatment of lead poisoning.

Comparative in vivo Lead Mobilization of meso‐ and rac‐2,3‐Dimercaptosuccinic Acids in Albino Wistar Rats

“…The rac-BATSA, 2 (48.0 g, 180.26 mmol) was hydrolyzed by adding 3N NaOH (480 ml) under nitrogen at 5" and then stirred for 2-3 min. at room temperature (22.5") as reported (Fang & Fernando 1995;Gerecke et al 1961). Caution: this hydrolysis is exothermic, therefore, cooling is required initially to maintain the temperature, especially for larger batches.…”

“…The results obtained in the syntheses demonstrate that a greater yield (18-25%) of the precursor ruc-BATSA (2) of ruc-DMSA (3) can be obtained by slight modifications in the work-up of the reported procedures (Fang & Fernando 1995;Gerecke et ul. 1961).…”

“…At the present time meso-2,3-dimercaptosuccinic acid (meso-DMSA), which is administered orally, is considered to be one of the most effective chelating agents for the treatment of chronic lead intoxication (Aaseth et al 1995;Aposhian & Aposhian 1990;Chisolm 1992;Graziano et al 1992;Liebelt et al 1994;Mortensen 1994). However, a recent study has clearly demonstrated that the stability constants for the lead complexes of rac-2,3-dimercaptosuccinic acid(rac-DMSA) are significantly greater than those of meso-DMSA (Fang & Fernando 1995). Previous studies comparing these two forms of DMSA have demonstrated the superiority of rac-DMSA to meso-DMSA as an antidote for experimental mercury intoxication in an animal model (Okonishnikova & Nirenburg 1970) and that the stability constant of the mercury complex with the rac-DMSA is greater than that of the mercury complex with meso-DMSA (Egorova et al 1972).…”

Use of the Caco-2 cell model to assess the relative lead-chelating ability of diasterioisomers of 2,3-dimercaptosuccinic acid.

“…The amount of meso-DMSA transported across the monolayer was not significantly different from background. These findings are consistent with the predictions pertaining to the relative lipophilicity of dl-DMSA compared with that of meso-DMSA made by Fang and Fernando (8 …”

“…The dl-DMSA form is soluble in water, strongly acidic solutions, and in nonaqueous solvents such as ethyl ether (7). On this basis it was proposed that dl-DMSA will be absorbed across the intestinal epithelium more efficiently than the meso diastereoisomer upon oral administration and that it may be a more effective chelator for the treatment of lead poisoning (8).…”