1. With revisions by Ms. Smith
Stereochemistry in
Drug Action (D.8)
and Drug Design (D9) By
Lisa Grossman
Max Krakauer
Sarah Theobald
With revisions by Ms. Smith

2. Drug Action (D.8)
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 beta-lactam ring action of penicillin
D.8.4 explain the increased potency of diamorphine (heroin) compared to morphine:

3. Review - What Are Stereoisomers?
two isomers
same molecular formula
same structural formulas
but
different spatial arrangements of atoms

4. The Two Types of Stereoisomers
Geometric isomers
Optical isomers

5. Geometric Isomers
Geometric isomers (or cis-trans isomers) are molecules with a double bond that form cis and trans isomers.
note that square planar molecules can also display geometric isomerism
cis and trans refers to the orientation of functional groups within a molecule

6. Geometric Isomers Cis (on the same side) Cis-2-butene
Molecular Formula- C4H8
Structural Formula- CH3CHCHCH3
Trans (across/opposite sides)
Trans-2-butene
Molecular Formula- C4H8
Structural Formula- CH3CHCHCH3
Different sides
Same side

7. Differences in Physical and Chemical Properties for Geometric Isomers
undergo different chemical reactions.
Stability (trans are usually more stable)
Polarity
Boiling/Melting point
Solubility

8. Geometric Isomers and Drugs
Because geometric isomers have different chemical and physical properties, they act differently as drugs in our bodies as well.
Example :
cis-platin used for chemotherapy - it can
enter cancer cells and interact with DNA
Trans- platin - not active

9. Optical Isomers Optical isomers have a chiral center
non-super imposable mirror images

10. Optical Isomers Terminology
Chiral: if a molecule is chiral ( or displays chirality) this means the molecule has two optical isomers
Chiral centre: the central carbon in an optical isomer with four bonds each attached to a different group.
Enantiomer: another name for a molecule that is found in optical isomers. For example, ibuprofen has a two enantiomers, a left rotating enantiomer and a right rotating enantiomer.
Racemic mixture: A mixture of 50% left rotating and 50% right rotating optical isomers

11. How can you tell if a molecule is chiral?
Optical isomers will always have a chiral (central) carbon with four single bonds each attached to a different substituent.
Example: Which molecule is not chiral?
CH3CHClOH
CH3CHCOOHNH2
BrCH2COOH

12. Using a Polarimeter
A polarimeter is a machine that can tell what optical isomer a substance contains by giving a rotational quantity in degrees
If the rotational value is positive the optical isomer is right handed.
If the rotational value is negative the optical isomer is left handed.

13. Using a Polarimeter
If a molecule rotates at +24 degrees, is it right handed or left handed?
Right
If a molecule rotates at -24 degrees, is it right handed or left handed?
Left
If a molecule rotates at 0 degrees, is it right handed or left handed?
Both-it is 50% Right and 50% Left
(This is called a racemic mixture.)

14. Optical Isomers and Drugs
Optical Isomers interact differently in our bodies because our bodies themselves are chiral.
Thus important to make sure you have the right optical isomers in your drugs.
Thalidomide tragedy- one enantiomer stops morning sickness in pregnant women. The drug was sold as a racemic mixture to reduce costs. However, it was later discovered that the other enantiomer causes severe birth defects.
Many drugs are still sold as a racemic mixture to reduce costs, including advil, motrin, and vitamin E.

15. D.8.3 Explain the importance of beta-lactam ring action of penicillin
R group
carboxylic acid group
Beta-lactam ring
heteroatomic four-membered ring
strained ring (90° vs 109.5°) is very
reactive
open ring binds with enzyme needed for
synthesis of linkages in bacterial cell walls
so… bacteria burst

16. D.8.4 explain the increased potency of diamorphine (heroin) compared to morphine:
two polar hydroxyl groups replaced by two less polar ester groups
more fat soluble
more readily absorbed into the non-polar environment of the central nervous system and the brain

17. Drug Design(D.9)
D.9.1 Discuss the use of a compound library in drug design.
D.9.2 Explain the use of combinatorial and parallel chemistry to synthesize new drugs
D.9.3 Describe how computers are used in drug design
D.9.4 Discuss how the polarity of a molecule can be modified to increase its aqueous solubility and how this facilitates its distribution around the body
D.9.5 Describe the use of chiral auxiliaries to form the desired enantiomer

18. Synthesis of New Drugs
often starts with ‘lead’ compound - pharmacologically active
uses organic chemistry to make small changes to the drug’s structure to produce a more effective drug
more potent, fewer side effects
result is a compound library – a collection of related compounds that can be tested for their pharmacological activity

19. Combinatorial Chemistry (Combi-Chem)
a way of synthesizing and testing potential new drugs that reduces time and costs
a set of reactants are reacted in all possible combinations
resulting compounds are cataloged by computers, called a compound (or combinatorial) library
library is tested in the laboratory en masse (all at once) for pharmacological activity
large libraries increase the chances of finding better drugs

20. Combinatorial Chemistry (Combi-Chem)
much of the process is streamlined with technology / computerization /
Robotics can be used to carry out identical chemical processes simultaneously
Known as “parallel synthesis”

21. Example of Synthesis in Combi-Chem: Synthesizing Polypeptides
amino acids (peptides) are the building blocks of protein molecules
amino acids are combined to make dipeptides in condensation reactions.
Peptide linkage
water

22. Example: Synthesizing Polypeptides
Because amino acids (peptides) contain both a carboxylic acid group and an amino group, two amino acids can be combined in four different ways to make dipeptides.
Peptide A-Peptide A
Peptide A-Peptide B
Peptide B-Peptide A
Peptide B-Peptide B

23. Example: Synthesizing Polypeptides
A simple two stage combi-chem reaction is used to make dipeptides.
Starts with a linking group attached to a plastic bead.
Plastic bead C H Cl

24. Example: Synthesizing Polypeptides
Stage one: the carboxylic acid group from an amino acid reacts with the Cl of the linking group… the amino acid now has its amine group ready to react
Plastic bead C H Cl +
amino
acid A =
amino acid A
+ HCl

25. Example: Synthesizing Polypeptides
Stage two: Product of previous reaction is washed and then reacted with aa B, forming a peptide bond… making a dipeptide.
Plastic bead C H
amino acid A
amino
acid B
amino acid B
+ H2O
dipeptide
Later, the plastic bead-CH2 is removed
to leave the dipeptide.

26. Example: Synthesizing Polypeptides
Next step?
Continue reactions to make polypeptides or
Remove the plastic bead-CH2 to leave the dipeptide.
Plastic bead C H
amino acid A
amino acid B
dipeptide

27. Example: Synthesizing Polypeptides
A typical two stage reaction in four containers 1 2 3 4
Stage 1
PB + aaA
PB + aaB
Stage 2
PBaaA + aaA
PBaaA + aaB
PBaaB + aaA
PBaaB + aaB
RESULT
A-A
A-B
B-A
B-B

28. Example: Synthesizing Polypeptides
a combination of two amino acids
makes 4 (22) dipeptides (two stages)
Using three amino acids,
makes 9 (32) dipeptides (two stages)
Using three amino acids (three stages)
makes 27 (33) tripeptides
Using three amino acids (four stages)
makes 81 (34) tetrapeptides

29. Example: Synthesizing Polypeptides
So the general formula for the total number of possible polypeptides formed is…
Number of amino acids = p
Number of stages in the reaction = s
Number of polypeptides formed = pS

30. Synthesizing other molecules ????
Scientists quickly realized that this methodology could be applied to other synthesis reactions.
Organic heterocyclics are often used as starting materials for potential drugs… with the addition of different branches often leading to new and better drugs.

31. How can Computers Help?
mode of drug action in the body usu involves interaction with biological molecules
enzymes
pharmacophore (receptor site)
molecular modeling software
more powerful, cheaper, more available
able to convert 2D structure into 3D structure
allows ‘virtual testing’ of drug with receptor site / enzyme
A drug may be an Inhibitor molecule (ligand)
interfer with active site of an enzyme…

32. Polarity of Molecules
In general, a drug that is altered to contain an ionic group is more soluble in aqueous solutions (like body fluids)… and therefore more effective.
However - some drugs that are fat soluble are more effective… if their target is the central nervous system… the brain… fatty cell membranes of nerve cells…
mescaline more potent than psylocybin
heroin more potent than morphine

33. Polarity of Molecules – Case in Point Aspirin
salicylic acid (2-hydroxybenzoic acid)
fever reducer, pain killer
strong acid
unpleasant to take orally
damaging to membranes
lining mouth, esophagus, stomach

34. Aspirin sodium salicylate fever reducer, pain killer
soluble ionic salt of salicylic acid
still bitter taste
still damaging to stomach
when it reverts to salicylic acid

35. Aspirin acetyl salicylic acid (ASA) fever reducer, pain killer
acetate (ethanoate) ester of salicylic acid
relatively tasteless
only weakly acidic
relatively insoluble

36. Aspirin acetyl salicylic acid (ASA) called a prodrug
Reacts with water
in basic environment of
small intestines
to form the active salicylic acid molecule.
also available as the sodium salt of ASA
more soluble… more effective

37. Synthesis of Drugs and Chirality
How drugs can be synthesized
Derivation from natural sources
Modification of natural substances
Laboratory synthesis
Usually only one enantiomer is found in nature, so naturally derived drugs usually contain an excess of one enantiomers while laboratory drugs are occasionally racemic mixtures

38. Chiral Auxiliaries
New: stereospecific synthesis or asymmetric synthesis
Stereospecific synthesis involves the use of chiral auxiliaries to make only one enantiomer of a molecule

39. What is a Chiral Auxiliary?
molecule that attaches itself chemically to the chiral molecule being synthesized
creates conditions which cause the drug synthesis to follow a certain stereospecific path – producing only one type of enantiomer
auxilary is removed or replaced to leave the desired enantiomer.

40. If you’re still confused, here’s a diagram
The top reaction is unmodified… the bottom reaction uses a chiral modifier…
Notice the different yields…. Much higher in bottom reaction.