Download Med Drugs 8 Keynote

http://www.compadre.org/Informal/index.cfm?Issue=122
Medicines and Drugs 8
Drug Action
1
Assessment Statements
D.8.1
Describe the importance of geometrical isomerism in drug action.
D.8.2
Discuss the importance of chirality in drug action.
D.8.3
Explain the importance of the beta-lactam ring action of penicillin.
D.8.4
Explain the increased potency of diamorphine (heroin) compared to morphine.
2
Fitting Molecules into Other Molecules
Here are FOUR important concepts related to
how the SHAPE of a drug (or part of a drug)
that will affect the ACTION of the drug:
1. geometric isomerism
2. chirality
!
3. polarity
4. ring strain
3
Review - Isomers
Isomers have the same molecular formula but
different structural formulas.
structural isomers
stereo isomers atoms/groups are in different
positions in the molecule
bonding pattern is the same,
BUT the position in SPACE
is different
e.g. propan-1-ol vs propan-2-ol
geometric isomers
e.g. but-1-ene vs but-2-ene
optical isomers
(cis trans isomers)
(need chiral carbons)
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1. Geometric Isomerism
All of these molecules have the molecular formula C4H8.
!
!
but-1-ene
a structural isomer
of the other two
!
trans-but-2-ene
cis-but-2-ene
these two are geometric isomers
Geometric isomers have different physical and chemical properties.
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1. Geometric Isomerism
Many transition metal complexes also show geometric isomerism.
http://cnx.org/content/m34480/latest/
cis form
(same side)
trans form
(opposite sides)
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1. Geometric Isomerism and Cisplatin
Cisplatin is an anti-cancer drug used to treat
ovarian and testicular cancers.
!
Cisplatin is a geometric isomer of a
complex ion of platinum diaminedichloroplatinum (II).
The molecular formula of this
compound is Pt(NH3)2(Cl)2
http://commons.wikimedia.org/wiki/File:Cisplatin-3D-balls.png
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1. Geometric Isomerism and Cisplatin
There are two geometric isomers of this compound:
The shape of these molecules
is square planar.
Both drugs are neutral
overall and can pass through
cell membranes.
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1. Geometric Isomerism and Cisplatin
Only the cis isomer has a therapeutic effect.
Once inside the cell, the Cl- ions are
exchanged for water molecules.
H2O +
In the nucleus, the cis forms bonds with
two Guanosine molecules on DNA.
This blocks the replication of DNA and
the virus dies.
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1. Geometric Isomerism and Cisplatin
The trans form is inactive.
NH3
Cl
Pt
Cl
NH3
The trans form does not have the correct orientation to bind to
two adjacent Guanosine molecules on DNA.
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2. Chirality
Recall:
Chiral molecules are non superimposable
mirror images of each other.
The two “mirror image” molecules are called enantiomers.
They occur whenever there are four different groups
bonded to a carbon atom (the “chiral carbon atom”).
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2. Chirality
Identify the chiral carbon in these drugs:
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2. Chirality
Enantiomers have different chemical properties ONLY
when they interact with other optically active materials.
Biological molecules are usually optically active.
Many drugs are optically active
(i.e. are optical isomers with a chiral carbon).
The two enantiomers have different chemical properties.
Only ONE enantiomer is therapeutic.
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2. Chirality
Taxol is an anti-cancer drug used to treat ovarian cancer.
Plants that produce useful
chiral drugs naturally will
only produce ONE
enantiomer.
http://www.elucidationimages.com/Portfollio/Portfollio%20Pages/yew.html
Consider: How does the natural production of a medically useful substance in
nature compare with the synthetic production of the same compound in the
laboratory?
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2. Chirality
When drugs are synthesized in
the laboratory, BOTH
enantiomers are produced.
This gives a RACEMIC MIXTURE,
where there are equimolar amounts
of both enantiomers.
RECALL: Different enantiomers of chiral
compounds have different chemical properties.
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2. Chirality
Thalidomide
anti-nausea
agent
limb
malformations
The synthetic production of thalidomide yields BOTH enantiomers.
Why is this a problem?
What are the implications for the drug development process?
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2. Chirality
Ibuprofen
Identify the chiral carbon.
What are the
implications?
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3. Ring Strain
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3. Ring Strain
Penicillin
Where is the beta lactam ring?
What is the hybridization of each
atom in the beta lactam ring
and the expected bond angle?
sp3 = 109.5º
sp2 = 120º
What are the actual bond angles?
90º
This puts a strain on the bonds, and makes them weaker.
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3. Ring Strain
Penicillin
The amide group is very reactive due to ring strain.
The amide group reacts with (and deactivates) the bacterial
enzyme transpeptidase that is needed to make bacterial cell walls.
This reaction is not reversible and bacterial cell growth stops.
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4. Polarity
Drug polarity is important in terms of:
1. ability to be transported through the blood and body tissues
• polar molecules are transported more easily
2. ability to pass through the blood brain barrier
(for CNS active drugs)
• nonpolar molecules pass through the blood brain barrier
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4. Polarity
The ester groups make
diamorphine less polar so
it penetrates the blood-brain barrier
more effectively and rapidly.
As a result, diamorphine is much more potent.
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