COORDINATION COMPLEXES

IN BIOLOGICAL SYSTEMS

Dr Karimah Kassim
 As therapeutic agents

• Metals are essential for healthy life, but their

concentration must stay between specific ranges that
vary from individual to individual.

• The necessary and allowable concentration of certain

metal cations in a human system is usually very small
(only a trace amount is usually needed), therefore these
metals are sometimes called trace metals.

• If the concentration of a metal falls outside of this narrow

concentration band, a disease state may occur.
 As therapeutic agents

• If a certain individual shows the symptom of deficiency of

a certain metal, for example the deficiency of iron leads
to aneamia, then the patient needs to take a certain high
dosage of iron (within the allowable prescribed dosage)
for a period of time to correct the deficiency.

• Once the deficiency is corrected, the disease will

disappear. However, if a patient displays symptoms of
heavy metal poisoning, then the way to treat the patient
is by prescribing chelating agents to reduce the high
concentration of metal ions in the system
Chelating agents used to remove certain
metal cations from biological systems

Chelating Agent Use/Comment

Dimercaprol Used to treat gold, mercury and arsenic poisoning
Ethylenediamine- Used to treat lead and heavy metal poisoning in farm
tetraacetate(EDTA) animals, spillage or contamination.
Disodium calcium Used to treat lead and mercury poisoning. The presence
edetate of Ca reduces the loss of calcium from the bones by
complexation with the EDTA.
Hydroxyurea Used in the treatment of some cancer.
D (-) penicillamine Chelates copper. Used in the treatment of Wilson’s
desease.
Cystanemine Chelates copper and iron. Used as a radioprotective agent.
Desferrioxamine Treatment of iron and aluminium poisoning.
 Metals as antibiotic
• The action of some antibiotic and antiviral drug is
believed to be due to their forming complexes with metal
ions.

• For example, practical evidence suggests that 8-

hydroxyquinoline used to treat skin rashes chelates iron
either inside the bacteria responsible for the rash or in
the cytoplasmic membrane to form a complex that is
toxic to the bacteria. 8-hydroxyquinoline forms 1:1, 1:2
and 1:3 complexes with iron, but it is believed that the
1:1 compound is the active complex
Formation of iron(II) monoxine, the active
complex for an antibiotic.

OH O Fe
N N
Fe2+

8-hydroxyquinoline (oxine) Iron(II) monoxine

 Metals as antibiotic

• Cadmium, nickel and zinc in high concentrations and

cobalt in all concentrations nullify the antibiotic effect of
8-hydroxyquinoline because these metals form more
stable non-toxic complexes with 8-hydroxyquinoline.

• Cisplatin is used to treat cancer of the testis, ovary,

squamous carcinoma of the bladder and drug-resistant
choriocarcinomas.
Heamoglobin
 Heamoglobin
• Heamoglobin (Hb) is a paramagnetic tetramer.

• The four monomers are conjugated proteins in which the

conjugated molecule is heam residue containing an
iron(II) ion surrounded by a porphine ring which is
responsible for the transportation of oxygen, carbon
dioxide and other small ligands.

• The ability of iron(II) of heamoglobin to coordinate with

small ligands such as H 2 O, O 2 , CO 2 , CO and CN - is
explained by the existence of an empty d orbital in the
iron. This d orbital is used for the d 2 sp 3 hybridization
which would explain the iron(II) six coordination.
 Heamoglobin
• The porphine ring is believed to be formed via an
electrophilic substitution of a pyrrole ring as shown in
Figure 2 below.

• The porphine molecule forms an important part of the

heamoglobin structure.

• Complexes derived from porphine are called porphyrins

and the iron-porphyrin combination is called the heam
group.

• Heamoglobin molecule contains four polypeptide chains,

each having one heam subunits. Heamoglobin carries
oxygen in the blood from the lungs to the tissues, where
it delivers the oxygen molecules to myoglobin, storing
oxygen for metabolic processes in muscles.
• Each of the four polypeptide chains in hemoglobin
contains a heam group that can bind to an oxygen
molecule.

• In deoxyhemoglobin, the affinity of each of the heam

group for oxygen is about the same.

• However, as soon as one of the heam groups becomes

oxygenated, the affinity of the other three heams for
oxygen is greatly enhanced.

• This phenomenon, called cooperativity, makes

hemoglobin a particularly suitable substance for the
uptake of oxygen in the lungs. Similarly, once a fully
oxygenated hemoglobin molecule releases an oxygen
molecule to myoglobin in the tissues, the other three
oxygen molecules will depart with increasing ease.
 Repeated
R R' electrophilic
R' R Electrophilic substitution and R NH N
Substitution other steps
R' NH HN R
N R N HN
H2N H R'
R
NH2
N Complexation
H2N H with Fe2+
Porphine Ring

HOCH2CH2
N N
NH N
Fe

N N
N HN HOCH2CH2

The Porphine Ring System Fe2+-porphyrin

(Heam)

Figure 2 : Formation of the heam and porphine ring from pyrrole

• The iron in the heam group has an oxidation number of
2+, coordinated to the 4 N in the porphine group and the
fifth coordination is to a histidine molecule.

• The histidine acts as a ligand which provides the

attachment to the protein.

• The sixth coordination is to a water molecule, which

binds to the Fe2+ on the side of the ring to complete the
octahedral arrangement. This heamoglobin molecule is
called the deoxyheamoglobin, as shown in Figure 3
below:
Structure of deoxyheamoglobin

Protein Deoxyheamoglobin
H H imparts a bluish tinge to
Water molecule
O venous blood. The water
ligand can be replaced
N N Porphine ring readily by a molecular
Fe
N N oxygen to form red
oxyheamoglobin found in
N Histidine group, arterial blood. Each
attaching the heam subunit contains a heam
HN group to the
protein
group, so each
heamoglobin molecule
can bind up to four O 2
molecules.
 Schematic diagram of oxygen and
carbon dioxide cycle in human

O2 to tissue
HbO2- Hb- + O2 TISSUE
Predominant form of
oxyhaemoglobin in arteries H+ CO2 from tissue
Predominant form or HHb H2O + CO2
heamoglobin in veins

HCO3-
 Processes of oxygen and carbon
dioxide cycle in human

• Heamoglobin acts as a buffer (maintaining the blood pH

at 7.4) in the transport of CO2 in the venous blood supply
to the lungs.

• Oxygen is not very soluble in water and is transported in

the form of a complex with haemoglobin.

• At the site of respiration, the oxygenated heamoglobin

supplies O2 to oxygen deficient tissues and accepts CO2
from carbon dioxide rich tissues (see Figure 4).
Processes of oxygen and carbon dioxide
cycle in human

• This CO2 is released into the blood where it dissolves to

form carbonic acid which dissociates to form H +
(lowering the pH value) and HCO3- ions.

• This ionization is promoted by the enzyme carbonic

anhydrase found in the erythrocyte of the blood. An
average human exhales between 20 to 40 moles of CO2
per day, producing a large amount of H + , therefore
venous blood must have a very high buffering capacity
since this gas exchange process can only occur at pH
value of very close to 7.4.
Processes of oxygen and carbon dioxide
cycle in human
• In the lungs, O 2 coordinates to the iron forming a six
coordinate complex which is then transported in the
blood to areas where there is a high CO2 content (high
PCO2) in the tissue.

• Here, pressure gradient exists which result in the

transfer of the O2 in the blood (high PO 2 ) to the tissue
(low PO 2 ) and CO 2 from the tissue (high PCO 2 ) to the
blood (low PCO2). The carbon dioxide is then
transported to the lungs where it is exchanged for
oxygen via the opposite process to the one described
above
Processes of oxygen and carbon dioxide
cycle in human
• Carbon monoxide (CO) poisoning is due the CO forming
stronger and more stable complex than O2 with
heamoglobin forming the very stable
carboxyhaemoglobin and so blocking the transport of
oxygen.

• Recall that the bond between M-CO is very strong

because of the p-backbonding form the metal to the CO
is synergically happening with the s-bonding from the
CO to the metal
 Toxicity of CO and CN- in heam
• Both CO and CN- are very good ligands towards iron and
so can interfere with normal working iron complexes in
the body.

• Carbon monoxide (CO) poisoning is due the CO forming

stronger and more stable complex than O2 with
heamoglobin forming the very stable
carboxyhaemoglobin and so blocking the transport of
oxygen.

• Recall that the bond between M-CO is very strong

because of the p-backbonding form the metal to the CO
is synergically happening with the s-bonding from the
CO to the metal
 Toxicity of CO and CN- in heam
• The mechanism for the toxicity of CN- ion is different.

• CN - coordinates to cytochromes oxidase (an iron

enzyme) that catalyzes the oxidation-reduction reactions
of certain cytochrome.

• The coordinated cyanide thus prevents electro transfer

process and rapid death results.

• Therefore, cyanide is called a respirotary inhibitor.