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 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)
SH S
M +

M
OH
HS OH S

•Side effects:
•Treatment for: •Cannot be used for: –GI
–As –Fe –Hypertension
–Hg –Cd –Lacrimation
–Au –Methyl Hg –Nephrotoxicity
–Pb –Se –Seizures
–Fever
Chelating Agent based on BAL
SH O
SH
O
HO
OH HS S OH
O SH
O

meso-DMSA DMPS
(R,S)-2,3-dimercaptosuccinic acid 2,3-dimercaptopropane-1-sulphonic acid

•Addition of carboxylic acid groups •Sulfonic acid group

•Less toxic •Less toxic than BAL
•Higher efficacy •Higher efficacy than BAL
•meso vs. rac •As, Cu, Pb, Hg
•As, Cu, Pb, Hg
Ethylenediaminetetraacetic
Acid (EDTA)

M+

EDTA EDTA-Metal Chelate

Ethylenediaminetetraacetic Acid •Side effects:
–Nephrotoxicity
•Divalent/Trivalent metals –Headaches
•Carboxylic Acids and Nitrogens –Fatigue
•Calcium or Zinc salts –Fever
•Fe, Mn, Pb –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 H OH O O

(CH2)5 N N (CH2)5
H2N N (CH2)5 N N
OH O O H 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 N N

N Fe-4 N
N Fe-4 N N Fe-4 N

N Fe+++ N
N N N
Fe+++ N 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
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