Chelation Therapy for Heavy Metal Intoxication

Jennifer M. CambreMedicinal ChemistryDr. John BuynakMarch 20, 2007

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

•Decrease in toxicity•Chelating agent toxicity•Formulation•Metabolism•Metal compartmentalization•High affinity for toxic metal•Low affinity for essential metals

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)

HS OH

SHM+

S

SOH

M

•Treatment for:–As–Hg–Au–Pb

•Cannot be used for:–Fe–Cd–Methyl Hg–Se

•Side effects:–GI–Hypertension–Lacrimation–Nephrotoxicity–Seizures–Fever

Chelating Agent based on BAL

HOOH

O

OSH

SH

HS S

SH

OH

O

O

2,3-dimercaptopropane-1-sulphonic acid

DMPSmeso-DMSA

(R,S)-2,3-dimercaptosuccinic acid

•Addition of carboxylic acid groups•Less toxic•Higher efficacy•meso vs. rac •As, Cu, Pb, Hg

•Sulfonic acid group•Less toxic than BAL•Higher efficacy than BAL•As, Cu, Pb, Hg

Ethylenediaminetetraacetic Acid (EDTA)

M+

EDTAEthylenediaminetetraacetic Acid

EDTA-Metal Chelate

•Divalent/Trivalent metals•Carboxylic Acids and Nitrogens•Calcium or Zinc salts•Fe, Mn, Pb

•Side effects:–Nephrotoxicity–Headaches–Fatigue–Fever–Increased urination

Diethylenetriaminepentaacetic acid (DTPA)

DTPADiethylenetriaminepentaacetic acid

•Effective for plutonium and acetinides•Increased affinity over EDTA•Side effects:

–Kidney problems–Intestinal mucosa–Liver problems

D-Penicillamine (DPA)

•Discovered by John Walshe•Cu, Pb, Au, Hg, Zn•Removes essential metals•Side effects: hematological disorders, GI problems, hepatotoxicity, nephotoxicity, and neurological disorders

Degradation of Penicillin

Deferoxamine (DFO)

H2 N(CH2)5

N

OH

O

O

N

H

(CH2 )5N

N

OH

O

O

H

(CH2)5

N

OH

O

•Trihydroxamine acid siderophore•Fe and Al toxicity•Side effects: hypotension, respiratory distress, tachycardia, tinnitus, hearing loss, vision loss, and shock•Dose-dependent toxicity

Iron Hexacyanoferrate - Prussian Blue

Fe-4

N

N

N

N

N

N

Fe-4

N

N

N

N

N

N

Fe-4

N

N

N

N

N

NFe+++

Fe+++

Fe+++ Fe+++

•Long term therapy•Radioactive cesium and all forms thallium•Side effects: constipation, binding of serum electrolytes

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

References1. Klaassen, C. D. The Pharmacological Basis of Therapeutics. 11th ed.; McGraw-Hill: New York,

2006.2. Goyer, R.A., Clarkson, T.W. Casarett and Doull's 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, 2683-2710.6. Peters, R. A, Stocken, L. A., Thompson, R. H. S. Nature 1945, 156, 616.7. Aposhian, H. A., Maiorino, R. M., Gonzalez-Ramirez, D., Zuniga-Charles, M., Xu, Z., Hurlbut, K.

M., Junco-Munoz, P., Dart, R. C., Aposhian, M. M. Toxicology 1995, 97, 23.8. Cantilena, I. R., Klaassen, C. D. Toxicol. Appl. Pharmacol. 1981, 58, 542.9. Singh, P. K., Xu, C., Jones, M. M., Kostial, K., Blanusa, M. Chem. Res. Toxicol. 1994, 7, 614.10. Stafford, B. T., Crosby, W. H. JAMA 1978, 239, 50.11. Piomelli, S., Rosen, J. F., Chisholm, J. J., Graef, J. W. J. Pediatr. 1984, 105, 523.12. Haust, H. L., Inwood, M., Spence, J. D., Poon, H. C., Peter, F. Clin. Biochem. 1989, 22, 189.13. Paul, M., Mason, R., Edwards, R. Res. Commun. Chem. Pathol. Pharmacol. 1989, 66, 441.14. Friedheim, E. A. H., DaSilva, J. R. Am. J. Trop. Med. Hyg. 1954, 3, 714.15. Kostial, K., Restek-Samarzija, N., Blanusa, M., Piasek, M., Prester, L. J., Jones, M. M., Singh, P.

K. J. Appl. Toxicol. 1997, 17, 71.16. Malorino, R.M., Atkins, J.M., Blaha, K., Carter, D.E., Aposhian, H.V. J. Pharmacol. Exp. Ther.

1990, 254, 570.17. Malorino, R. M., Bruce, D. C., Aposhian, H. V. Toxicol. Appl. Pharmacol. 1989, 97, 338.18. Aposhian, H.V., Aposhian, M. M. Annu. Rev. Pharmacol. Toxicol. 1990, 30, 279.19. McNeill Consumer Products Company, Chemet product information. ed.; McNeill Consumer

Products Co.: Fort Washington, 1994; 'Vol.' p.20. Wiederman, P., Fichtl, B., Szinicz, L. Biopharm. Drug Dispos. 1982, 3, 267.21. Maiorino, R. M., Xu, Z. F., Aposhian, H. V. J. Pharmacol. Exp. Ther. 1995, 277, 375.22. Aposhian, H. V., Maiorino, R. M., Rivera, M., Bruce, D. C., Dart, R. C., Hurlbut, K. M., Levine, D.

J., Zheng, W., Fernando, Q., Carter, D., Aposhian, M. M. Clin. Toxicol. 1992B, 30, 505.

References23. Zalups, R. K., Parks, L. D., Cannon, V. T. Mol. Pharmacol. 1998, 54, 353.24. Brownie, C. F., Brownie, C., Noden, D., Krook, L., Haluska, M., Aronson, A. L. Toxicol. Appl.

Pharmacol. 1986, 82, 426.25. American Academy of Pediatrics Committee on Drugs, Pediatrics 1995, 96, (155).26. Seaton, C. L., Lasman, J., Smith, D. R. Toxicol. Appl. Pharmacol. 1999, 159, 153.27. Netter, P., Bannwarth, B., Pere, P., Nicholas, A. Pharmacokinet. 1987, 13, 317.28. Walshe, J. M. Am. J. Med. 1956, 21, 487.29. Shannon, M. W., Townsend, M. K. Ann. Pharmacother. 2000, 34, 15.30. Walshe, J. M. Assessment of Treatment of Wilson's Disease with Triethylene Tetraamine 2HCl

(trien 2HCl)`. ed.; Raven Press: New York, 1983; 'Vol.' p 243-261.31. Brewer, G. J. Drugs 1995, 50, 240.32. Dubois, R. S., Rodgerson, D. O., Hambridge, K. M. J. Pediatr. Gastroenterol. Nutr. 1990, 10, 77.33. Walshe, J. M. Lancet 1982, 1, 643.34. Keberle, H. Ann. NY Acad. Sci. 1964, 119, 758.35. Allain, P., Mauras, Y., Chaleil, D., Simon, P., Ang, K.S., Cam, G., LeMignon, L., Simon, M. Br. J.

Clin. Pharmacol. 1987, 24, 207.36. Winship, K. A. Adverse Drug React. Toxicol. Rev. 1993, 12, 177.37. Dragsten, P. R., Hallaway, P. E., Hanson, G. J. J. Lab. Clin. Med. 2000, 135, 57.38. Kontoghiorghes, G. J. Analyst 1995, 120, 845.39. Thompson, D. F., Callen, E. D. Ann. Pharmacother. 2004, 38, 1509.40. Hoffman, R. S. Toxicol. Rev. 2003, 22, 29.41. Lehmann, P. A., Favari, L. J. Toxicol. - Clin. Toxicol. 1984, 22, 331.42. Bradberry, S. M., Vale, J. A. J. Toxicol. - Clin. Toxicol. 1999, 37, 259.43. Kargacin, B., Blanusa, M., Arezina, R., Kostial, K., Singh, P. K., Jones, M. Bull. Environ. Contam.

Toxicol. 1991, 47, 160.44. Kojima, S., Ono, H., Furukuawa, A. Arch. Toxicol. 64, 91.