chelation therapy for heavy metal intoxication jennifer m. cambre medicinal chemistry dr. john...

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

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