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Transcript of Chelation Therapy for Heavy Metal Intoxication Jennifer M. Cambre Medicinal Chemistry Dr. John...
![Page 1: Chelation Therapy for Heavy Metal Intoxication Jennifer M. Cambre Medicinal Chemistry Dr. John Buynak March 20, 2007.](https://reader036.fdocuments.us/reader036/viewer/2022081513/56649ebe5503460f94bc79cb/html5/thumbnails/1.jpg)
Chelation Therapy for Heavy Metal Intoxication
Jennifer M. CambreMedicinal ChemistryDr. John BuynakMarch 20, 2007
![Page 2: Chelation Therapy for Heavy Metal Intoxication Jennifer M. Cambre Medicinal Chemistry Dr. John Buynak March 20, 2007.](https://reader036.fdocuments.us/reader036/viewer/2022081513/56649ebe5503460f94bc79cb/html5/thumbnails/2.jpg)
Introduction
• Chelation therapy basics
• Designing chelating agents
• Metal intoxication
• Chelating agents
![Page 3: Chelation Therapy for Heavy Metal Intoxication Jennifer M. Cambre Medicinal Chemistry Dr. John Buynak March 20, 2007.](https://reader036.fdocuments.us/reader036/viewer/2022081513/56649ebe5503460f94bc79cb/html5/thumbnails/3.jpg)
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 toxicity•Chelating agent toxicity•Formulation•Metabolism•Metal compartmentalization•High affinity for toxic metal•Low affinity for essential metals
![Page 5: Chelation Therapy for Heavy Metal Intoxication Jennifer M. Cambre Medicinal Chemistry Dr. John Buynak March 20, 2007.](https://reader036.fdocuments.us/reader036/viewer/2022081513/56649ebe5503460f94bc79cb/html5/thumbnails/5.jpg)
Metal Toxicity
• Toxic effects due to metal’s:– 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
![Page 9: Chelation Therapy for Heavy Metal Intoxication Jennifer M. Cambre Medicinal Chemistry Dr. John Buynak March 20, 2007.](https://reader036.fdocuments.us/reader036/viewer/2022081513/56649ebe5503460f94bc79cb/html5/thumbnails/9.jpg)
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
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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
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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
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Diethylenetriaminepentaacetic acid (DTPA)
DTPADiethylenetriaminepentaacetic 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)
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
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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 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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