Option D
D.8 drug action
Some aspects of molecular
structure that affect the action of
a drug
• stereo isomerism
o geometric (cis/trans)
o optical isomerism (enantiomers)
• strain in ring structure
• molecular polarity (solubility and uptake)
Example: Geometric isomerism in
diaminedichloro platinum (II) complex
ion used in a drug
cisplatin
• can act as an anti-cancer
drug because of its
orientation, it can bond
with DNA in the nucleus of
cancer cells and cause the
cell to die.
transplatin
• cannot act as an antic-cancer
drug as nitrogen atoms are
too far apart to react with
DNA – no pharmaceutical
effect – actually toxic to body
Inorganic transition complex
with a square planar shape,
900 bond angles and dative
covalent bonds
Optical isomerism
• Synthesis of chiral drug molecules in laboratories produces
racemic mixtures i.e. equimolar solution of both
enantiomers.
• These are known as “in vitro” drugs.
• Such drugs were often prescribed as racemic mixtures or
racemates.
• Each enantiomer also has different biological activity as they
behave differently with other chiral molecules in the body.
• Pharmaceutical companies must analyze effects of each
isomer, and determine if it should be marketed as a racemate
or if they need to then produce the single enantiomer.
• Some enantiomers are harmful to humans.
Optical isomerism
(2/3 of drugs on the market are chiral!)
Carbon atoms in ring structures (in which there is
no delocalization to have 4 different atoms) can
also be chiral if the part of the ring on one side of
the carbon atom is different from the part of the
ring on the other side of the carbon atom.
Each side of a ring is classified as a different
group if, when moving around the ring from the
chiral centre or carbon, the order of atoms is
different each way. It is said the chiral atom has
two different views around the ring.
thalidomide
Identify the chiral carbon
in the structure below
• One enantiomer (R)
alleviates morning
sickness in pregnant
women and induced
sleep and calmness
• Other enantiomer (S) is a
teratogenic - causes
deformities in the fetus
•
Later discovered that administering
just the R enantiomer was no good
either. It is able to turn into S inside
the body.
thalidomide
Identify the chiral
carbon in the structure
below
This carbon has the N-ring, two
different sides of the benzene
structure, and a H (not shown)
How many chiral centres in fluoxetine?
More examples of chiral drugs
• Ibuprofen: one enantiomer is more effective than
the other – identify the chiral centre in your data
booklet (in vitro)
• DOPA: this is a drug which is used in the treatment
of Parkinson disease; one isomer is effective whilst
the other isomer has no physiological effect
• Fluoxetine (Prozac) – used to treat depression (in
vitro)
• Morphine/codeine/heroin: there are 5 chiral
centres in each of these molecules; only one
enantiomer is analgesic. (in vivo – only one
enantiomer b/c harvested naturally)
beta-lactam ring in penicillin
a four-membered
square ring structure
which contains an
amide group
(-CONH-) and consists
of one nitrogen atom
and three carbon
atoms (and two
hydrogen atoms).
beta-lactam ring
• For each carbon and the
nitrogen atom, identify
the type of hybridization
and preferred bond
angles around each
atom.
• Referring to bond angles
say why the ring is a
strained structure
What causes the strain?
• As a result of the sp3 hybridisation of two of
the three carbon atoms and the single
nitrogen atom and the sp2 hybridisation of the
third carbon atom, the preferred bond angles
are 109 and 120.
• However, the bond angles in the beta-lactam
ring are reduced to only 90° and this puts the
beta-lactam ring structure under strain
weakening the bonds.
beta-lactam ring
(between
the N and the
sp2 C)
• Strains makes ring reactive.
• Ring easily breaks open in the amide group,(in
the presence of an enzyme such as
transpeptidase) to form covalent bonds with
the transpeptidase.
• This deactivates the transpeptidase that
synthesizes the bacterial cell walls, thus
inhibiting the growth of bacterial cell walls.
• As a result water enters the bacteria cell
causing it to burst due to increased osmotic
pressure.
beta-lactam ring
Sad 
Happy 
Drug Structure and Solubility
• Drugs need to efficiently reach target
receptors in the body.
• Body is water soluble environment so water
soluble drugs are good and can reach blood
stream.
• If CNS is the target, drug needs to reach brain.
– Brain is surrounded by a “blood-brain” barrier
which protects it from restricting what can enter
from the blood. It is hydrophobic, and non-polar
so polar molecules cannot easily cross.
Why is Heroin more potent than morphine?
morphine
• Two hydroxyl groups
heroin
• Both hydroxyl groups
replaced by ester groups
Heroin more potent than morphine
• Diamorphine is less polar than morphine as it
does not have the polar hydroxyl groups
anymore but two less polar ester groups.
• Diamorphine (heroin) cannot form any
hydrogen bonds and is therefore less soluble
in polar substances such as water but more
soluble in non-polar fatty tissue, which makes
up the central nervous system.
• Heroin can therefore cross the blood-brain
barrier faster/more easily than morphine.