You
may have imagined that medicines were mainly organic molecules, but compounds of
the precious metals are increasingly being used to treat a number of illnesses
from rheumatoid arthritis to some forms of cancer.
This article
discusses the characteristic properties of these transition metals which gives
them their medicinal properties.
Most
of the d-block elements in the periodic table are believed to be essential for
mammalian life. The elements Titanium (Ti) to Copper (Cu) show characteristic
properties of transition metals including:
·
Formation
of compounds in a variety of oxidation states
·
Formation
of coloured compounds
·
Catalytic
activity of the element
·
Strong
tendency to form complexes
The
heavier elements in the d-block are often more toxic as they bind to small
molecules irreversibly (the complexes formed are very stable) and block
essential processes. But in certain circumstances this can be used as an
advantage and lead to therapeutic benefits. Compounds of the precious metals
Silver (Ag), Gold (Au) and Platinum (Pt) are being used alongside organic
compounds in the fight against infection and disease.
(Ag)
The antibacterial properties of silver were recognised even before an understanding of bacteria had developed. From ancient times it was known that water kept in silver vessels would remain drinkable for quite along time. These anti bacterial properties were not due to the actual metal but the release of Ag+ ions into solution.
Silver nitrate and colloidal silver preparations began to be used
during the last century to prevent infection of wounds. However, silver chloride
was not very soluble producing a precipitate of this compound. This lead to
ionic imbalances in the body, producing undesirable side effects.
In the late sixties a new silver compound was introduced, silver
sulphadiazine. This is an insoluble compound which is formulated as a cream.
The silver ions are released from the compound slowly at a very low
concentration, so avoiding most of the side effects. This cream is still being
used today to prevent infection when treating burns. Silver ions display a broad
spectrum of activity against bacteria, but how it does so is still not known for
certain. Silver ions may bind to DNA; they may also affect the cell membrane of
bacteria.
Developments are underway to try to use silver as coating for
devices implanted in the body, such as replacement joints. It is critical for
the success of these applications that silver ions should be released slowly
over a long period, and this release is not blocked by absorption of proteins
onto the surface of the implant. Whether this will be successful or not is
unclear but it is certain that more silver compounds with antibacterial
properties will be developed in the future and will play an important role in
the world of medicine.
(Au)
Rheumatoid
arthritis is a disease affecting the joints. It is caused by a malfunction in
the immune system, the complex array of chemicals and cellular agents that
provide defence against infections. The immune system releases degradative
enzymes that attack the joints. As a result the membrane and cartilage are
damaged, causing pain and inflammation of the joints. Eventually the cartilage
is destroyed and the surfaces of the bones become damaged. Fibrous tissue builds
up reducing mobility and eventually closing the joints altogether. Although this
disease is more common in old people it can strike at any age and can affect all
the joints in the body. It is a very painful disease, which causes great
suffering for the patient.
In
it’s initial stages rheumatoid arthritis is treated with anti-inflammatory
agents such as aspirin. If the disease progresses more potent medicines are
required and in many instances gold compounds are used.
There
are two gold-containing medicines in use:
1.
Sodium
Aurothiomalate ~
a polymeric compound of gold in which the sulphur atoms form bridges between the
gold atoms.
2.
Auranofin
~ not a
polymer, exists as small molecules.
Aurothiomalate
is administered by an intra-muscular injection, while Auranofin is taken orally.
Scientists believe that one feature of the chemistry of
gold is the key to its therapeutic action, it can interact with enzymes that
attack the joint tissues by complexing with their free –SH groups. But
unfortunately the gold medicines have a number of undesirable side effects, such
as skin rashes and gastrointestinal disturbance, which have prevented their
wider use in treating rheumatoid arthritis.
PLATINUM
(Pt)
The application of
platinum compounds in cancer treatment has been the most recent development in
the use of precious metals in medicine.
The earliest indications of this use of platinum came from
experiments by Professor Rosenberg of Michigan State University, USA in the
1960s. Rosenberg was studying the effects of electromagnetic fields on cell
division when he noticed that the bacteria he used to test the equipment had
grown into long filaments. Some factor in his experiment was inhibiting cell
division in the bacteria, while not restricting cell growth. He later discovered
that the effect was due to small quantities of platinum dissolving from the
electrodes he used to generate the electromagnetic field. This lead to an
important discovery. The platinum ions produced reacted in the growth medium to
form a variety of Pt(II) and Pt(IV) complexes, such as cisplatin. It was these complexes which inhibited cell division.
Professor Rosenberg (in collaboration with the National Cancer Institute in the
USA) then demonstrated that the cisplatin possessed anti-tumour properties, due
to its ability to interfere with the synthesis of DNA.
Cisplatin is a square planar complex of platinum in its +2
oxidation state. Platinum forms very stable bonds with nitrogen donor ligands.
It is thought that, When cisplatin reacts with DNA the two chloride ligands are
replaced by two guanine bases in neighbouring positions of one strand of DNA,
bonding through nitrogen. The formation of this complex distorts the structure
of DNA and prevents its replication (synthesis of a new strand of DNA).
In the late seventies the drug was licensed by regulatory health
bodies, in the USA and the UK, for use in the treatment of some forms of cancer.
It does however have a number of unwanted side effects such as damage to the
kidneys and nervous system and gastrointestinal disturbance. As a result it is
essential that the correct dosage is administered and the patient is carefully
monitored during treatment. Cisplatin is generally used in combination with
other medicines and is one of the most widely used anti-cancer agents. It is
most effective in the treatment of testicular and ovarian cancers.
Despite cisplatin’s widespread use, its unpleasant side-effects
severely restrict its application. The compound containing
1,1-cyclobutanecarboxylic was chosen as a preferred clinical candidate and is
now known as carboplatin. At normal
doses it causes minimal damage to the kidneys and nerves but its use is limited
as it also causes a loss of blood cells. It is used mainly in the treatment of
ovarian cancer.
Both cisplatin and carboplatin have to be given by intravenous
injection, as they are poorly absorbed when taken orally. In order to achieve
oral absorption (which would be more convenient for the patient) new complexes
have been developed, again using the platinum (IV) Oxidation State.
Modern
biotechnology is now starting to provide us with natural molecules that assist
the body’s defence against disease. As research continues more closely
resembling natural molecules will be developed to replace today’s medicines,
but until then metal compounds will continue to provide precious medicines to
treat the ailments of many patients.
By Brenda Murphy/Y13: Chemistry Department, Loreto College, Coleraine
