Stereoisomeric selectivity of 2,3-dimercaptosuccinic acids in chelation therapy for lead poisoning.
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.
Fang
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Department of Chemistry, University of Arizona, Tucson 85721, USA.
Fernando
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D002614:Chelating Agents / Q000737:chemistry* / Q000627:therapeutic use; D006863:Hydrogen-Ion Concentration; D007854:Lead / Q000737:chemistry; D007855:Lead Poisoning / Q000188:drug therapy*; D008024:Ligands; D011199:Potentiometry; D012964:Sodium / Q000737:chemistry; D013055:Spectrophotometry, Infrared; D013237:Stereoisomerism; D004113:Succimer / Q000737:chemistry* / Q000627:therapeutic use
D002614:Chelating Agents; D008024:Ligands; D007854:Lead; D012964:Sodium; D004113:Succimer