CHEM F343

Inorganic Chemistry III

Prof. R. Krishnan
BITS Pilani Hyderabad Campus
Metal Complex – DNA Binding
 Tris(phenanthroline) metal complexes

 Bind to the double helix by intercalation in the major groove and

 Bind through hydrophobic association in the minor groove
[Rh(phen)3]3+
[Ru(bpy)3]3+
 [Ru(phen)3]2+ and DNA interaction
Enantiomeric discrimination in binding to DNA

Preference for ∆-[Ru(phen)3]2+ upon intercalation

 [Ru(phen)3]2+ and DNA interaction
Enantiomeric discrimination in binding to DNA

Preference for Λ-[Ru(phen)3]2+ upon groove binding

 ∆-[Ru(phen)3]2+ bind DNA through intercalation
Λ-[Ru(phen)3]2+ bind DNA through groove binding

Ru(phen)2Cl2 binds to DNA covalently, preference for guanine

site. Chiral preference for Λ-isomer.

Rh(phen)2Cl2 binds to DNA covalently, photoactivation

needed.
DNA Binding Preferences of Metal Complexes

Cis-(NH3)2PtCl2 or cis-(NH3)2Pt(en)2+ do not intercalate

[(phen)Pt(en)]2+ and [(bpy)Pt(en)]2+ do intercalate

[Cu(phen)2]+ bind through minor groove (not intercalation)

 Intercalation

Binding in the minor grooves

 [Ru(phen)3]2+ and DNA interaction
[Ru(phen)3]2+:
MLCT transition, λmax = 447 nm ( ε = 1.9 x 104 M-1 cm-1 )
Emission, λem = 610 nm (τ = 0.6 μs in aerated aqueous solution)

UV-Visible spectrum
Absorbance & Intensity shift

On DNA intercalation:
Hypochromism in MLCT band
Increased emission intensity and life time
[Ru(phen)3]2+:
MLCT transition, λmax = 447 nm ( ε = 1.9 x 104 M-1 cm-1 )
Emission, λem = 610 nm (τ = 0.6 μs in aerated aqueous solution)

Luminescence characteristics of [Ru(phen)3]2+

with DNA binding:

Free [Ru(phen)3]2+ (broken line)

Λ- [Ru(phen)3]2+ and DNA (dotted line)
∆- [Ru(phen)3]2+ and DNA (solid line)
 Spectroscopic Probe

Dppz = dipyridophenazine
DIP = 4,7-diphenyl-1,10-phenanthroline

 No luminescence outside
 No binding of B-form of DNA with - DNA.
form.  Luminescence (>104) with
 Selective binding with -form only. DNA intercalation.
 Reactions with Nucleic Acids

 Redox reaction of the metal complex that mediates

oxidation of the nucleic acid.

 Coordination of the metal center to the sugar-phosphate

backbone – mediate hydrolysis of the polymer.
[Ru(phen)3]2+ bound to DNA: oxygen-dependent alkaline-
sensitive strand cleavage on photolysis.

[Rh(phen)2(phi)]3+: Oxygen-dependent photolytic DNA

cleavage. (phi = 9,10-phenanthrenequinone diimine)
Hydrolytic Cleavage
Metal Toxicity
Metal ion concentration and
physiological effect
 Some Metal-related diseases

• Hemochromatosis (excess Fe)

• Alzheimer’s disease (Cu-amyloid plaques formation)
• Wilson’s disease (Cu intolerance)
• Menkes’ disease (Cu deficiency)
• Acrodermatitis enteropathica (Zn deficiency)
• Lethal milk syndrome (Zn deficiency)

23
 Heavy Metals
Heavy metals are toxic to human health
Most common heavy metals are
 Lead(Pb)
 Mercury(Hg)
 Cadmium(Cd)
 Arsenic(As)
• They are mainly produced by industrial activities, and
deposit slowly in the surrounding water and soil
 Mercury
• Most volatile of all metals
• Highly toxic in vapor form
• Liquid mercury itself is not highly toxic, and
most of that ingested is excreted
 Source of Mercury
 Elemental mercury is employed in many applications
due to its unusual property of being a liquid that
conducts electricity
 Used in electrical switches, fluorescent light bulbs and
mercury lamps
 Emission of mercury vapor from large industrial
operations
 Unregulated burning of coal and fuel oil
 Incineration of municipal wastes
 Emissions from mercury containing products:
batteries, thermometers, etc.
 Mercury amalgams: dental fillings
Mercury: Health Effects

 Skin burns
 Irritation of nose and skin
 Rashes
 Excessive perspiration
 Damage to the kidneys
 Damage to vision
 Minamata disease
 Dysfunctions of the central nervous system
 Loss of hearing and muscle coordination
 Severe brain damage
 Death
Mercury:
Mercury-Resistant Bacteria:
 LEAD (Pb)
Source of Lead
 Commonly used in the industry building for roofing
and flashing, and for soundproofing
 Used in pipes
 When combined with tin, it forms solder, used in
electronics and in other applications to make
connections between solid metals
 Lead is also used in ammunition
Note: Lead shots have been banned in United States,
Canada, Netherlands, Norway and Denmark
 Lead is used in batteries and sinkers in fishing
 LEAD (Pb)
Source of Lead
 Used in paints
Lead chromate is the yellow pigment used in paints usually
applied to school buses.
Lead is also used in corrosion-resistant paints and has a
bright red color
 Used in ceramics and dishware
The leaching of lead from glazed ceramics used to prepare
food is a major source of dietary lead, especially in Mexico
 In the past, lead salts were used as coloring agents in
various foods
 Lead is used in some types of PVC mini-blinds
 LEAD (Pb)
Health Effect

• At high levels, inorganic lead is a general metabolic

poison
• Lead poisoning effects the neurological and
reproductive systems,
• Lead breaks the blood-brain barrier and interferes with
the normal development of brain in infants
 LEAD (Pb)
Health Effect

• Lead is observed to lower IQ levels in children

• Lead is transferred postnatally from the mother
in her breast milk
• At elevated levels, lead poisoning would
eventually result in death
 LEAD (Pb)
Lead Poisoning
• The human groups most at risk of lead poisoning are
fetuses and children under the age of seven
• Chronic lead poisoning from wine and other sources is one
of the factors in the downfall of the roman empire
• Episodes of lead poisoning were recorded through the
middle ages and even until recent times
• A recent study in Mexico indicated that pregnant women
can decrease the lead levels in their blood and presumably
in the blood of their developing fetus by taking calcium
supplements.
 CADMIUM (Cd)

o Cadmium is mined and then released into the environment

mainly through the air during smelting.

o Once in the environment, cadmium moves easily through

the soil and is taken up into the food chain.

o Certain plants, such as tobacco, rice, other cereal grains,

potatoes, and other vegetables, take up cadmium from the
soil.
 CADMIUM (Cd)

Source of Cadmium

 Cadmium is used as an electrode in “NiCad” batteries

 Cadmium is used as a pigment in paints(yellow color)
 It is also used in photovoltaic devices and in TV screens
 Cigarette smoke
 Fertilizers and pesticides
Note: The greatest proportion of our exposure to
cadmium comes from our food supply- seafood, organ
meats, particularly kidneys, and also from potatoes,
rice, and other grains.
 CADMIUM (Cd)

 Cadmium lies in the same subgroup of the periodic table as

zinc and mercury, but is more similar to zinc
 Coal burning is the main source of environmental cadmium
 Incineration of wastes containing cadmium is an important
source of the metal in the environment
 Cadmium is most toxic in its ionic form unlike mercury
Note: Mercury is most toxic in vapor form. Lead, cadmium
and arsenic are most toxic in their ionic forms.
 ARSENIC (As)

• Arsenic oxides were the common poisons used

for murder and suicide from roman times
through to the middle ages
• Arsenic compounds were used widely as
pesticides before the organic chemicals era
• Arsenic is very much similar to phosphorous
 ARSENIC (As)

Sources of Arsenic

 Pesticides
 Tobacco smoke
 Mining, smelting of gold, lead, copper and nickel
 Production of iron and steel
 Combustion of coal
 Leachate from abandoned gold mines
 Used as a wood preservative
 Herbicides
 Wallpaper paste and pigments in wallpaper
 ARSENIC (As)

Health Effects

 Birth defects
 Carcinogen:
Lung cancer results from the inhalation of arsenic
and probably also from its ingestion. Skin and liver
cancer, and cancers of the bladder and kidneys, arise
from ingested arsenic
 Gastrointestinal damage
 Severe vomiting
 Diarrhea
 Death
 CADMIUM (Cd)

Health Effects

• Severe pain in joints

• Bone diseases
• Kidney problems
• Its lifetime in the body is several years
• In very high levels it poses serious health problems
related to bones, liver and kidneys and can
eventually cause death.
 ARSENIC (As)

 Metallic arsenic not toxic –

 insoluble in water and acids
 Its compounds are toxic, its effect known since ancient
times
 Used as a pesticide, in industry
 Absorption via guts or skin – systemic toxicity
 Excretion via urine
 Deposition in skin, in nails and hair for many years
 If administered in low doses – addiction - mithridatism
 ARSENIC (As)

Mechanism of action:
-Trivalent compounds most toxic (pentavalent less)
-Binds to –SH groups – block of many enzymes (oxidative
phosphorylation, glycolysis)
-Damage of mucosa, endothelium,
-Increased permeability of vessels, decrease in blood
pressure

Clinical signs:
-Peracute poisoning (within a few seconds to a few minutes):
- collapse of blood circulation, dilatation of vessels,
sometimes vomiting and diarrhoea
 ARSENIC (As)

-Acute poisoning:
- violent stomach pains, tenderness and pressure, retching,
vomiting, sense of dryness and tightness in the throat, thirst,
hoarseness and difficulty of speech
- the matter vomited, greenish or yellowish, sometimes
streaked with blood
- convulsions, delirium, death due to circulatory collapse
-Chronic poisoning:
- strong profuse diarrhoea, inappetence, dehydration
- changes in skin colour, formation of hard patches on the
skin
- skin cancer, lung cancer, cancer of the kidney and bladder
 Heavy Metal Toxicity

 Hg is highly toxic in vapor form but Pb, Cd and As are

more toxic in their cationic form
 Toxicity arises from strong affinity of the heavy metal
cations for sulfur
 Chelation Therapy

Chelation (KEE-LAY-SHUN) comes from the Greek word

– “chele”- which means claw.
“the use of a chelating agent to bind with a metal in the
body to form a metal chelate complex so that the metal
loses its toxic effect or physiological activity”
 Heavy Metal Toxicity

 Medicinal treatment for heavy metal poisoning is

done by chelation therapy by administering
compounds known as chelates

Example :
 British Anti-Lewisite(BAL),
 Ethylene diamine tetraacetic acid(EDTA).
 Heavy Metal Toxicity

2,3-Disulfanylpropan-1-ol
2,3-Dimercaptopropanol
Dimercaprol
British anti-Lewisite (BAL)

It is used medically in treatment of arsenic, mercury, gold,

lead, antimony.
 Arsenic (As) Toxicity

Treatment:
 Dimercaprol,
 Sodium thiosulphate,
 Trace Element Measurement

 Most common method of collecting particulate

matter is through filters
 Identification and concentration of individual trace
metals like lead, cadmium, arsenic, mercury and
chromium is determined by
 Atomic absorption spectrophotometer
 X-ray fluorescence
Hemochromatosis: a rare genetic disease that results in the
overabundance of iron in the liver, brain, heart and kidneys,
causing liver dysfunction, diabetes, changes in skin
pigmentation, heart problems, arthritis and testicular atrophy

Sickle cell disease: an inherited genetic disorder that causes

red blood cells to take on a characteristic crescent or sickle-
like shape with decreased ability to carry oxygen

Sideroblastic anemia: a condition in which there is excess iron

in the bone cells

Thalassemia intermedia: a genetic form of anemia in which

there is an abnormality in the oxygen carrying portion of red
blood cells
 Iron Poisoning
Chelation Therapy

2 HOOC-CH2-CH2-COOH + 3 H2N-CH2-CH2-CH2-CH2-CH2-NH2

Desferrioxamine
 Iron Poisoning
Chelation Therapy
Wilson's disease: an inherited (autosomal recessive) disorder
where excessive quantities of copper build up in the body,
particularly in the liver and central nervous system.

Chelation therapy by penicillamine

PENICILLAMINE

The pharmaceutical form is D-penicillamine, as L-penicillamine is toxic.

It is sold under the trade names of Cuprimine and Depen.
PENICILLAMINE COPPER COMPLEX
PENICILLAMINE COPPER COMPLEX
 Excess Zinc
• Probably competes with copper and iron in the organism
• Decreased serum copper
• Decreased utilisation of oxygen, oxidative stress
• Decreased ceruloplasmin
• Decreased antioxidant
• Decreases glutathione levels

Treatment:
 Eradication of metal particles from stomach,
administration of Na2CO3 , formation of insoluble ZnCO3
 EDTA
 Blood transfusion in severely anaemic patients
 Chelation Therapy

• Chelation therapy has primarily been used

as agent to detoxify metals ions.
• EDTA binds to these metal ions because of
its strong affinity for cations.
• The bound metal ions are then excreted in
the urine.
 Chelation Therapy

• Chelation therapy must be used with supplementation of

calcium
• There have been a few deaths recorded related to
hypocalcemia as a result of chelation therapy
stroke- calcium facilitates the conversion of prothrombin 
thrombin
heart attacks – calcium helps to regulate heartbeats
 Excess Calcium
• Atheromatous plaque is one of the leading
causes of Coronary Artery Disease (CAD).
• A major component of plaque is calcium.
• 3-Theories of plaque removal:
– EDTA might break up atheromatous plaque.
– EDTA may activate a hormone that sets calcium free.
– Chelation therapy may reduce oxidative stress on walls
of blood vessels.
 Thallium (Tl)
• Used for making low-melting point special glass for highly
reflective lenses
• In developing countries still permitted as a pesticide
(rodenticide, insecticide)
• Body absorbs thallium very effectively, especially through
the skin, lungs
• Two-phase elimination – most within 24 hours in urine, but
the rest stays for weeks and is excreted via faeces
• Undergoes enterohepatic circulation
• Cummulated in brain, kidneys, bones

Treatment:
Prussian blue - Fe7(CN)18(H2O)x
– formation of non-soluble complexes that are excreted in bile
– fluid therapy to maintain kidney function
 Metal Toxicity

Metal Route of Entry Toxicity Effect

Irritation of respiratory system,

Inhalation and
Arsenic Liver and Kidney damage, Loss of
ingestion
appetite, nausea and vomiting etc

Inhalation and Lung, liver and kidney damage;

Cadmium
ingestion Irritation of respiratory system

Inhalation, ingestion,
Lung damage and Irritation of
Chromium and absorption
respiratory system
through skin
 Metal Toxicity

Metal Route of entry Toxicity Effect

Irritation of respiratory
Inhalation, ingestion and
Mercury system; lung, liver and
absorption through skin
kidney damage

Lung and liver damage;

Lead Inhalation and ingestion
loss of appetite, nausea etc

Lung, liver and kidney

Nickel Inhalation
damage