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Chelation therapy:
What is chelation therapy?

Detoxification of metal ions by using suitable chelating agents is known as chelation

therapy.Chelation therapy is the preferred medical treatment for reducing the toxic effects of
metals. Chelating agents are capable of binding to toxic metal ions to form complex
structures which are easily excreted from the body removing them from intracellular or
extracellular spaces.

Choice of ligands in chelation therapy:

Several points of concern appears important for choice of ligands in chelation therapy, some of
these are-

1. Identification of the site of action of the toxic elements.

2. Identification of the donor groups which bind the metal, the hard-soft acid-base principle is
often useful in this respect.

3. Looking for the chelating agents with similar donor groups as those in the binding site for the
toxic metal.

4. The resulting complex should be able to free the inhibited site and be able to carry the metal
up to its excretion stage. This requires that the complex should be stable, should not be
metabolized and be water soluble.

5. The chelating agent should be non-toxic itself and should specifically bind the toxic metal.

The chelation therapy may be subdivided into two classes –

A) Use of chelating agents or ligand to remove toxic metals from the body.

B) Use of metal chelate.

Chelating agents as drugs: Numbers of chelating agents are used as antidotes for metal
poisoning. Such chelating agents have appropriate number of ionisable functional groups,
usually –OH, -COOH, -SO3H, -SH in their structures, so that the resulting metal complexes have
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an overall charge. The drugs should be hydrophilic in nature, so that these could be easily
excreted through urine. A few examples are discussed here.

• 1. BAL:

The arsenic bearing compound, Lewisite, ClCH=CHAsCl2

Was used as a poisonous gas during the 2nd world ware.

Its antidote is 2,3-dimarcapto propanol, which is popularly known as British Anti –Lewisite
(BAL).

BAL is binds to arsenic strongly and removes it from the system in the form of the complex as
shown below-

SH Cl H2C S
H2C AsCH CHCl
+ 2HCl
+ AsCH CHCl HC S
HC SH

OH Cl H2C OH
H2C

BAL can show its additional activity in acute Cu-poisoning and in Wilson’s disease. At present
BAL is widely used and administered intramuscularly for the treatment of metal poisoning
caused due to mercury, antimony, bismuth, copper and gold etc.

Adverse Effects

• Low therapeutic index (small margin of safety)

• Tendency to redistribute arsenic to brain

• Need for (painful) intramuscular injection

• Unpleasant odour (rotten eggs!)

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• Common adverse effects include fever, conjunctivitis (eye inflammation), lacrimation

(tearing), constricted feeling (chest, limbs, jaw, abdomen), headache, and pain at the
injection site.

• More serious complications include infections at the injection site, liver damage, elevated
blood pressure and heart rate, and hemolysis (destruction of red blood cells) BAL should
be avoided in pregnancy if possible.

Because of adverse effect BAL is not at all a good chelating drug. In fact, with the
advent of dmpa and dmps the clinical use of BAL is going to be phased out.

Unithiol (2, 3-dimercapto-1-propane sulfonic acid, dmps):

• This water soluble drug has sevsrsl advantages compared to BAL. because of the clinical
advantages such as water solubility, stability, high LD50 value (i.e. less toxicity), strong
complexing power, unithiol is more promising to detoxify the soft metals like As, Hg, Tl,
etc.

• In the detoxification of CH3Hg+, BAL can lead to enhance the toxicity but unithiol can
safely use. The corresponding CH3Hg-unithiol complex being charged cannot pass
through the biological membrane.
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Disodium meso 2, 3-dimercaptosuccinate (dmsa)

• It is soluble in water and can be given in drinking water. It is of low toxicity and its LD50
value is about 30 times higher than that of BAL. In detoxification of CH3Hg+, it is quit
promising. It can detoxify many other soft metals.

COO-Na+
CH SH

HC SH

COO-Na+

Disodium meso 2, 3-dimercaptosuccinate (dmsa)

D-Penicillamine (DPA) and N-acetyl D-penicilamine (NAPA):

• D-penicilamine is 3-mercaptovaline (i.e., 3, 3’-dimethyl cysteine). The D-isomer is

therapeutically active but the L-isomer is toxic. By using the binding sites, S, N, O it can
bind with Hg (II), CH3Hg (II), Cu (II), Au (I), Pb (II), etc.

• Its LD50 value is much higher than that of BAL and it can be orally administered. In
NAPA, the presence of an actyl group makes it more lipophilic.

• This is why to remove CH3Hg+ from the erythrocyte cells; NAPA is more effective than
DPA.

(H3C)2C SH O

HC NH C CH3
O C OH

D-Penicillamine (DPA) N-acetyl D-penicilamine(NAPA)

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Metal chelate as drugs:

• Free ethylene diamine tetraacetic acid (H4EDTA) is toxic and causes reduction of
calcium level in blood. But its disodium monocalcium salt, (Na2CaEDTA), could be
injected intravenously.

• It is widely used for the treatment of lead poisoning, whereby, lead-EDTA complex,
Na2Pb EDTA, together with unreacted Na2CaEDTA are excreted through urine.

PbII -Enz. + Na2CaEDTA CaII -Enz. + Na2PbEDTA

• The drug is used for the treatment of poisoning due to zinc and radioactive strontium.

• Fe (II)-EDTA complex is used as an antianaemic drug. CaH2EDTA is employed for the

removal of stone from urinary tract. Usually these stones consist of calcium oxalate and
calcium phosphate.

Cis-platin, or cis-diamminedichloroplatinum(II)(CDDP):

• Cis-platin, or cis-diamminedichloroplatinum(II)(CDDP) is a chemotherapy drug. It was

the first member of a class of platinum-containing anti-cancer drugs, which now also
includes carboplatin and oxaliplatin. These platinum complexes react in vivo, binding to
and causing cross linking of DNA, which ultimately triggers apoptosis (programmed cell
death).

• Discovery

• The compound cis-[Pt(NH3)2(Cl)2] was first described by Michele Peyrone in 1845, and
known for a long time as Peyrone's salt. The structure was deduced by Alfred Werner in
1893.

• In 1965, Barnett Rosenberg, van Camp et al. of Michigan State University discovered
that electrolysis of platinum electrodes generated a soluble platinum complex which
inhibited binary fission in Escherichia coli (E. coli) bacteria. Although bacterial cell
growth continued, cell division was arrested, the bacteria growing as filaments up to 300
times their normal length.
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• The octahedral Pt(IV) complex cis-[PtCl4(NH3)2], but not the trans isomer, was found to
be effective at forcing filamentous growth of E. coli cells. The square planar Pt (II)
complex, cis-[PtCl2(NH3)2] turned out to be even more effective at forcing filamentous
growth.

• This finding led to the observation that cis-[PtCl2(NH3)2] was indeed highly effective at
regressing the mass of sarcomas in rats.

• Confirmation of this discovery and extension of testing to other tumour cell lines
launched the medicinal applications of cisplatin. Cisplatin was approved for use in
testicular and ovarian cancers by the U.S. Food and Drug Administration on 19
December 1978.,and in the UK (and in several other European countries) in 1979.

• Medical use

• Cisplatin is administered intravenously as short-term infusion in normal saline for

treatment of solid malignancies. It is used to treat various types of cancers,
including sarcomas, some carcinomas (e.g. small cell lung cancer, and ovarian
cancer), lymphomas, bladder cancer, cervical cancer and germ cell tumours.

• Cisplatin is particularly effective against testicular cancer; the cure rate was improved
from 10% to 85%.

• Preparation of cis-platin

• The synthesis of cis-platin starts from potassium tetrachloroplatinate. The tetra iodide is
formed by reaction with an excess of potassium iodide.

• Reaction with ammonia forms K2[PtI2(NH3)2] which is isolated as a yellow compound.

When silver nitrate in water is added insoluble silver iodide precipitates and
K2[Pt(OH2)2(NH3)2] remains in solution. Addition of potassium chloride will form the
final product which precipitates.In the triiodo intermediate the addition of the second
ammonia ligand is governed by the trans effect.
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Mechanism of anticancer drug, cis-platin

▪ It is establish that binding of cis-platin with DNA bases destroys the double helix DNA
structure.

▪ The main target of cis-platin is to interact with the DNA bases and should hydrolyse at
the right place after the passive diffusion though the cell membrane.

▪ If it hydrolyses in the blood stream before it reaches the target site within the cells, it will
react with nonspecific target site available to it.

▪ The compound is both thermodynamically and kinetically stable with respect to

hydrolysis in blood where the concentration of Cl- is fairly high (Ca.0.1M).

▪ After entering through the cell membrane, it hydrolyses in cytoplasm where the
concentration of Cl- is very low (Ca.4mM).

▪ The hydrolysis products are kinetically activated to interact with the DNA bases- as
shown below-
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NH3 Cl Cl
Passive diffusion through Cl
pt 0
3.4A
pt
the cell membrane
NH3 NH3 NH3
Cl

(in cytoplasm
(cis-platin)
low [Cl-])
(in venous blood
high [Cl-]) H2O

(hydrolysis
i.e. aquation)
Cl-

+
+ 2+ OH2
OH2 OH2 NH3
NH3 NH3 pt
pt pt
H2O NH3 Cl
NH3 HO NH3 H2O Cl-

Activated forms of cis-platin

DNA (Cancer cell)

Binding with the DNA -bases to induce winding, bending and H-bond
rupture in the structure(i.e., replication of DNA is prevented)

Mode of binding of cisplatin with DNA

▪ Binding of cis-platin with DNA bases can occur in different possible ways:

▪ 1. Intrastand linking in which the platinum centre bridges the two adjacent guanine bases
on a single DNA chain.

▪ 2. Pt-centre may bind with the adjacent guanine and adenine bases at the cis-positions.

▪ 3. interstand cross-linking in which the platinum centre bridges the DNA bases on the
opposite stands of DNA.
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▪ 4. A didentate chelation by a single base like guanine.

it has been experimentally establish that among the different possible routes of cis-platin-
DNA interaction , the most important route involves the intrastand cross-linking by two adjacent
guanine(G) from a single DNA strand.
+
OH2
NH3
pt
-A-P-G-P-G-P-C- NH3 HO
-A-P-G-P-G-P-C-
-T-P-C-P-C-P-G-
Pt
NH3
NH3

• Schematic representation of intrastand cross-linking by cis-platin with

DNA. (G = guanine, C= cytosine, A= Adenine, T = thymine, P =
phosphate)

OR,
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H3 N Cl

Pt
Cl
H3N

H3N Cl A T
0
Pt 3.4A NH3
H2 O
T A
Cl Fast
H3N
Pt
G NH3
C H2O
2H2O
C G
slow

A T
2Cl-

A T

T A
C NH3
G
NH3 Pt
Pt
C G NH3
H 3N
A T

ANTI CANCER ACTION OF CIS-DDP

• In cis-platin, the distance(called bite distance) between the cis-ligands is about 300pm
which can be maintained by the adjacent DNA-bases like guanine(acting as ligand) on a
single strand.

• This matching between the geometrical parameters of cis platin and DNA structure favors
the interaction of the two adjacent DNA bases as cis ligands with pt(II) centre.
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The bite distance between the trans-chloride ligands is about 400pm which is too long for
coordination by adjacent DNA-bases of a particular strand.

Side effect of cis-platin: Cis-platin has a number of side-effects that can

limit its use:

• Nephrotoxicity (kidney damage) is a major concern.

The nephrotoxicity of platinum-class drugs seems to be related to reactive oxygen

species and in animal models can be ameliorated by free radical scavenging agents.
Nephrotoxicity is a dose-limiting side effect.

• Neurotoxicity:

Neurotoxicity (nerve damage) can be anticipated by performing nerve conduction studies before
and after treatment.

• Common neurological side effects of cis-platin include visual perception and hearing
disorder, which can occur soon after treatment begins.

• Nausea and vomiting:

• Ototoxicity (hearing loss):

There is at present no effective treatment to prevent this side effect, which may be severe.
Audiometric analysis may be necessary to assess the severity of ototoxicity. Other drugs
(such as the aminoglycoside antibiotic class) may also cause ototoxicity, and the
administration of this class of antibiotics in patients receiving cis-platin is generally avoided.

Carboplatin, or cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II):

Carboplatin, or cis-diammine(1,1cyclobutanedicarboxylato)platinum(II) (trade

names Paraplatin and Paraplatin-AQ)
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It is a chemotherapy drug used against some forms of cancer (mainly ovarian carcinoma, lung,
head and neck cancers as well as bladder, breast and cervical; central nervous system or germ
cell tumours; osteogenic sarcoma, and as preparation for a stem cell or bone marrow transplant).

It was introduced in the late 1980s and has since gained popularity in clinical treatment due to its
vastly reduced side effects compared to its parent compound cis-platin. Cisplatin and carboplatin
belong to the group of platinum-based antineoplastic agents, and interact with DNA to interfere
with DNA repair.

Chemistry:

In terms of its structure, carboplatin differs from cisplatin in that it has a bidentate dicarboxylate
(the ligand is CycloButaneDiCarboxylic Acid, CBDCA) in cisplatin. in place of the
two chloride ligand, which are the leaving groups.

• For this reason, "CBDCA" is sometimes used in the medical literature as an abbreviation
referring to carboplatin. Carboplatin exhibits lower reactivity and slower DNA binding
kinetics, although it forms the same reaction products in vitro at equivalent doses with
cisplatin.

• The diminished reactivity limits protein-carboplatin complexes, which are excreted. The
lower excretion rate of carboplatin means that more is retained in the body, and hence its
effects are longer lasting (a retention half-life of 30 hours for carboplatin, compared to
1.5-3.6 hours in the case of cis-platin).
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Side effect:

• Relative to cisplatin, the greatest benefit of carboplatin is its reduced side effects,
particularly the elimination of nephrotoxic effects. Nausea and vomiting are less severe
and more easily controlled.

• The main drawback of carboplatin is its myelosuppressive effect. This causes

the blood cell and platelet output of bone marrow in the body to decrease quite
dramatically, sometimes as low as 10% of its usual production levels.

• The nadir of this myelosuppression usually occurs 21–28 days after the first treatment,
after which the blood cell and platelet levels in the blood begin to stabilize, often coming
close to its pre-carboplatin levels.

• Carboplatin is less potent than cisplatin; depending on the strain of cancer, carboplatin
may only be 1/8 to 1/45 as effective. The clinical standard of dosage of carboplatin is
usually a 4:1 ratio compared to cisplatin; that is, for a dose that usually requires a
particular dose of cisplatin, four times as much carboplatin is needed to achieve the same
effectiveness.

• The stable property of carboplatin is a mixed blessing: once uptake of the drug occurs,
its retention half-life is considerably longer than cisplatin, but it is also this inertness
that causes carboplatin to go right through the human body, and up to 90% of the
carboplatin given can be recovered in urine

Gold complex:
The application of gold compounds to medicine is called "chrysotherapy" and
"aurotherapy.“

• The first reports of research in this area appeared in 1935, primarily to

reduce inflammation and to slow disease progression in patients with rheumatoid
arthritis.
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• The use of gold compounds decreased since the 1990s because of numerous side effects
and monitoring requirements, limited efficacy, and very slow onset of action. Most
chemical compounds of gold, including some of the drugs discussed below, are not, in
fact, salts but are examples of metal thiolate complexes.

• Sodium aurothiomalate (INN, known in the United States as gold sodium thiomalate)
is a gold compound that is used for its immunosuppressive anti-
rheumatic effects.Along with an orally-administered gold salt, auranofin, it is one of
only two gold compounds currently employed in modern medicine.

Sodium aurothiomalate Auranofin,

Adverse effects:

• Its most common side effects are-

• Digestive: mostly dyspepsia, mouth swelling, nausea, vomiting and taste disturbance.

• Vasomotor: mostly flushing, fainting, dizziness, sweating, weakness,

palpitations, shortness of breath and blurred vision.

• Dermatologic: usually itchiness, rash, local irritation near to the injection site and hair
loss in nature, although conjunctivitis, blood dyscrasias, kidney damage, joint
pain, muscle aches/pains and liver dysfunction are also common.