Chelation Therapy Presentation Web

Chelation Therapy for Heavy Metal Intoxication Jennifer M. Cambre Medicinal Chemistry Dr. John Buynak March 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 AntiLewisite – 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 AntiLewisite – BAL) SH

M

S

+

M HS

•Treatment for: –As –Hg –Au –Pb

OH

S

OH

•Side effects: •Cannot be used for: –GI –Fe –Hypertension –Cd –Lacrimation –Methyl Hg –Nephrotoxicity –Se –Seizures –Fever

Chelating Agent based on BAL SH

SH

O

O

HO OH O

HS

S

SH meso-DMSA

(R,S)-2,3-dimercaptosuccinic acid •Addition of carboxylic acid groups •Less toxic •Higher efficacy •meso vs. rac •As, Cu, Pb, Hg

OH

O DMPS 2,3-dimercaptopropane-1-sulphonic acid •Sulfonic acid group •Less toxic than BAL •Higher efficacy than BAL •As, Cu, Pb, Hg

Ethylenediaminetetraacetic Acid (EDTA) M+

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

EDTA-Metal Chelate •Side effects: –Nephrotoxicity –Headaches –Fatigue –Fever –Increased urination

Diethylenetriaminepentaacetic acid (DTPA)

DTPA Diethylenetriaminepentaacetic 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) O H2N

H

(CH2)5

OH

N N OH

(CH2)5 O

O

O

N N O

H

(CH2)5 N OH

•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 N N

N

N Fe-4

N Fe-4

N

Fe+++ N

Fe+++

N

N Fe-4

N

N N

N

N

N

N Fe+++

N

Fe+++

N

•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

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.

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