Chelation Therapy for Heavy Metal Intoxication

1
Chelation Therapy for Heavy Metal Intoxication

• Jennifer M. Cambre

Medicinal Chemistry Dr. John Buynak March 20, 2007
2
Introduction

• Chelation therapy basics
• Designing chelating agents
• Metal intoxication
• Chelating agents

3
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

4
Designing Chelating Agents

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

5
Metal Toxicity

• Toxic effects due to metals
• Reduction/oxidation potential
• Acid/base chemistry
• Structural/ligand properties

6
Metal Toxicity

• Toxic effects depend on
• Nutritional status
• Age
• Gender
• Route of exposure
• Amount
• Tissue distribution
• Accumulation
• Excretion

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Metal Toxicity

• Mechanisms of toxicity include
• Inhibition of enzymes
• Inhibition of protein synthesis
• Changes in nucleic acid functioning
• Changes in cell membrane permeability

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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

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Dimercaprol (British Anti-Lewisite BAL)
M

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

• Treatment for
• As
• Hg
• Au
• Pb

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

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Chelating Agent based on BAL
DMPS
meso-DMSA
2,3-dimercaptopropane-1-sulphonic acid
(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

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Ethylenediaminetetraacetic Acid (EDTA)
M
EDTA-Metal Chelate
EDTA
Ethylenediaminetetraacetic Acid

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

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

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Diethylenetriaminepentaacetic acid (DTPA)
DTPA
Diethylenetriaminepentaacetic acid

• Effective for plutonium and acetinides
• Increased affinity over EDTA
• Side effects
• Kidney problems
• Intestinal mucosa
• Liver problems

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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

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Degradation of Penicillin
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Deferoxamine (DFO)

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

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Iron Hexacyanoferrate - Prussian Blue

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

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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

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