Stereoisomeric selectivity of 2,3-dimercaptosuccinic acid in chelation therapy for heavy metal poisoning

Racemic-2,3-dimercaptosuccinic acid (rac-DMSA){dollar}sp1{dollar} was synthesized and its structure in the solid state was studied by single crystal X-ray analysis. The three-dimensional structure of rac-DMSA solid is stabilized by van der Waals forces, whereas the meso-DMSA solid is stabilized by hydrogen bonding. This accounts for the drastic difference in the solubilities of DMSA stereoisomers. The behavior of DMSA stereoisomers in aqueous solution were studied by potentiometric titration, IR and {dollar}sp1{dollar}H NMR. Rac-DMSA irreversibly converts to the meso form at an elevated temperature under acidic conditions. Two mechanisms were proposed to explain the conversion. At high pH rac-DMSA tends to form ion-paired complexes with alkaline counter ions via two carboxylate groups. At physiological pH DMSA stereoisomers form two intramolecular six-membered rings.; The formation constants and the structures of lead and zinc chelates of DMSA stereoisomers formed in aqueous solution were determined by potentiometric titration, IR and {dollar}sp1{dollar}H NMR. Lead and zinc complex with rac-DMSA to a greater extent than with meso-DMSA. DMSA stereoisomers tend to form dimeric chelates with Zn{dollar}sp{lcub}2+{rcub}{dollar}, but monomeric chelates with Pb{dollar}sp{lcub}2+{rcub}{dollar}. In the zinc chelates of rac-DMSA two bulky carboxylate groups of the ligand have a staggered anti-relation, whereas in the zinc chelates of meso-DMSA two carboxylate groups assumes a staggered gauche-relation. This accounts for that the formation constants of zinc chelates of rac-DMSA are invariably larger than those of the corresponding chelates of meso-DMSA. The binding sites in PbL of DMSA stereoisomers are two thiolate groups and one carboxylate group of the ligands. In the lead chelates of the stereoisomers of DMSA, rac-DMSA exists in a staggered anti-conformation, but meso-DMSA favors a staggered gauche-conformation with respect to the bulky carboxylate groups. This accounts for that the formation constants of the lead chelates of rac-DMSA are invariably larger than those of the corresponding chelates of meso-DMSA. On the basis of our studies ZnL{dollar}sb2{dollar} chelate of rac-DMSA has been proposed to be a more effective lead chelator than meso-DMSA for therapeutical use.