2. D8.1 Describe the importance of geometrical
isomerism in drug action
What is geometrical isomerism? (cis-trans isomerism)
A form of isomerism where atoms are bonded in the same order
but are arranged differently in space
Inorganic - usually occurs in octahedral or square planar
structures
Organic
Isomerism that occurs when there is restricted rotation
around a bond so that the position of atoms cannot change.
-Double C=C bonds (but also in inorganic double bonds)
3. D.8.1
Two important types: Cis and Trans
Cis - same side, Trans - same side
4. D.8.1
Whether a molecule is a cis isomer or trans isomer can
create different pharmacological effects
Consider the isomers of diamminedichloroplatinum(ii):
Cisplatin
is highly effective in treating testicular and ovarian
cancers while transplatin is not very effective
5. D.8.1
-Both molecules contain no overall charge so they can
diffuse through the cell membrane
-Once inside, Cl- exchanged for H2O to make
[Pt(NH3)2Cl(H2O)]+ so it can enter the nucleus
-Inside the nucleus, only the cis
isomer has the correct
orientation to bind the the cancer
cell's DNA.
This alters the cell's DNA, so
when it tries to replicate, it can't
be copied correctly and dies
6. D.8.2 Discuss the importance
of chirality in drug action.
Optical isomers are the mirror image of one another, so
that their structures cannot be superimposed (in other
words, if it is asymmetric)
These are called chiral molecules, and their different
structures are called enantiomers
The term ‘chiral’ is derived from the Greek word for
‘handedness’ – ie. right-handedness or left-handedness.
Your hands are chiral: your right hand is a mirror image of
your left hand, but if you place one hand on top of the
other, both palms down, you see that they are not
superimposable.
7. D.8.2
Chiral carbon atoms in molecules form
two optically active isomers.
Because of the different stereochemistry,
the two enantiomers act in different ways
in the body.
Different isomers can also interact
differently with disease organisms.
8. D.8.2
In synthetic drugs, both enantionmers
are created, making a racemic mixture
(50% of both isomers)
Currently there is no effective way to
separate the two enantiomers from
each other within a synthetic drug
because the two are identical in nearly
every way
9. D.8.2
Therefore, many drugs produce
harmful side effects
EX: Thalidomide has two enantiomers
1. Alleviates morning sickness
2. Causes deformities in the limbs of fetuses
Scientists now study the effects of
both enantiomers when new drugs are
synthesized
11. D.8.2
However, not all racemic mixtures have harmful
effects on the body and sometimes one enantiomer
will provide the desired pharmacological properties
while the other will have no effect on the body
EX: Amino acid, DOPA’s L-isomer is an intermediate
in dopamine biosynthesis and is given to patients to
help manage Parkinson’s Disease
-The D-isomer has no biological effect on the
body
12. D.8.3 Explain the importance of
the beta-lactam ring action of
penicillin
Beta lactim rings are four membered
lactim rings (basically a cyclic amide)
The amide group is attached to the
beta carbon relative to the carbonyl
It is part of the core structure of many
antibiotics, and generally work by
inhibiting bacterial cell wall
biosynthesis.
13. D.8.3 cont.
They are more reactive to hydrolysis
conditions than linear amides.
14. D.8.3 Explain the importance of
the beta-lactam ring action of
penicillin
All penicillin contains a 4-membered
beta-lactam ring containing two
carbon atoms that are sp³ hybridized,
a nitrogen atom that is sp³ hybridized,
and a carbon atom that is sp²
hybridized.
Restrictions of the ring cause normal
bond angles (109.5 and 120) to not
occur
16. D.8.3 Cont.
Amide group in the ring is highly
reactive is a result of the ring being
readily able to break due to the
strained angles.
When the ring opens, the penicillin
becomes covalently bonded to the
enzyme that synthesizes bacterial cell
walls, thus blocking its action
17. D.8.4 Explain the increased
potency of diamorphine (heroin)
compared to morphine
Heroin is more potent and produces
greater feelings of euphoria
Caused by the difference in the
polarity of the two substances.
18. D.8.4 cont.
Morphine contain 2 polar –OH groups
When it is converted to heroin, these are
replaced by ethanoate groups (less polar)
Heroin, subsequently, is more soluble in
lipids (non-polar)
Thus, it’s able to penetrate the lipid-based
blood-brain barrier and reach the brain in
higher concentrations than morphine.
