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Chelation Therapy for Heavy Metal Intoxication Jennifer M. Cambre Introduction Chelation therapy basics Designing chelating agents Metal intoxication Chelating agents What is Chelation Therapy? Definition Chelation agent + Metal Chelate Available electrons to form bond Coordination bond L M Makes sense to chemist Differences in biological systems Designing Chelating Agents Metal Toxicity Toxic effects due to metal’s: Reduction/oxidation potential Acid/base chemistry Structural/ligand properties Metal Toxicity Toxic effects depend on: Nutritional status Age Gender Route of exposure Amount Tissue distribution Accumulation Excretion Metal Toxicity Mechanisms of toxicity include: Inhibition of enzymes Inhibition of protein synthesis Changes in nucleic acid functioning Changes in cell membrane permeability Dimercaprol (British Anti-Lewisite – BAL) World War II poisoning antidote 1st chelating agent used clinically Most toxic Forms mercaptide bond Targets kidneys, cardiovascular system, and central nervous system Dimercaprol (British Anti-Lewisite – BAL) Chelating Agent based on BAL Ethylenediaminetetraacetic Acid (EDTA) Diethylenetriaminepentaacetic acid (DTPA) D-Penicillamine (DPA) Degradation of Penicillin Deferoxamine (DFO) Iron Hexacyanoferrate - Prussian Blue Conclusion Main stay of metal intoxication treatment Low commerical priority Expensive development Medium sales Future research Molecular mechanisms Distribution of chelating agents Combination therapy Essential metal binding Decreased toxicity References 1. Klaassen, C. D. The Pharmacological Basis of Therapeutics. 11th ed.; McGraw-Hill: New York, 2006. 2. Goyer, R.A., Clarkson, T.W. Casarett and Doulls Toxicology: The Basic Science of Poisons. 6th ed.; McGraw-Hill: New York, 2001. 3. Williams, H. B. W. Clin Toxicol 1982, (19), 1081-1115. 4. Blanusa, M., Varnai, V.M., Piasek, M., Kostial, K. Current Medicinal Chemistry 2005, 12, 2771-2794. 5. Andersen, O. Chem Rev 1999, 99, 2683-271