Chelation Therapy Presentation Web

8/14/2019 Chelation Therapy Presentation Web

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Chelation Therapy for Heavy

Metal Intoxication

Jennifer M. Cambre

Medicinal Chemistry

Dr. John Buynak

March 20, 2007


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Introduction

Chelation therapy basics Designing chelating agents

Metal intoxication

Chelating agents


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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


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Designing Chelating Agents

Decrease in toxicityChelating agent toxicityFormulationMetabolismMetal compartmentalizationHigh affinity for toxic metal

Low affinity for essential metals


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Metal Toxicity

Toxic effects due to metals:

Reduction/oxidation potential

Acid/base chemistry Structural/ligand properties


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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)

HS OH

SHM+

S

S

OHM

Treatment for:

AsHgAuPb

Cannot be used for:FeCdMethyl HgSe

Side effects:

GIHypertensionLacrimationNephrotoxicitySeizures

Fever


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Chelating Agent based on BAL

HO

OH

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 groupsLess toxicHigher efficacymeso vs. racAs, Cu, Pb, Hg

Sulfonic acid groupLess toxic than BALHigher efficacy than BALAs, Cu, Pb, Hg


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Ethylenediaminetetraacetic

Acid (EDTA)

M+

EDTA

Ethylenediaminetetraacetic Acid

EDTA-Metal Chelate

Divalent/Trivalent metalsCarboxylic Acids and NitrogensCalcium or Zinc saltsFe, Mn, Pb

Side effects:NephrotoxicityHeadachesFatigueFeverIncreased urination


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Diethylenetriaminepentaacetic

acid (DTPA)

DTPADiethylenetriaminepentaacetic acid

Effective for plutonium and acetinidesIncreased affinity over EDTASide effects:

Kidney problemsIntestinal mucosa

Liver problems


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D-Penicillamine (DPA)

Discovered by John WalsheCu, Pb, Au, Hg, ZnRemoves essential metalsSide effects: hematological disorders, GI problems, hepatotoxicity,

nephotoxicity, and neurological disorders


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Degradation of Penicillin


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Deferoxamine (DFO)

H2N

(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 toxicitySide effects: hypotension, respiratory distress, tachycardia, tinnitus,

hearing loss, vision loss, and shockDose-dependent toxicity


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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 therapyRadioactive cesium and all forms thalliumSide 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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