Narrated PowerPoint presentation explaining chirality in relation to drug-receptor interactions

1. Stereochemistry of Drugs
Jim Mitroka, Ph.D.

3. Isomers: types

4. Molecules are 3D!
2D 3DSimulated 3D

5. Stereoisomers: terms
• Stereoisomers – molecules with the same type and
bonding location of atoms but different
arrangement of atoms in space
• Chiral – compound that lacks a plane of symmetry,
generally will have a carbon atom with 4 unique
substituents (see accompanying video demo)
• Enantiomers – the two stereoisomers that exist for
a chiral molecule. Mirror images of each other.
– racemates - 50:50 mixtures of enantiomers
– homochiral: one enantiomer only

6. Bond designation for stereochemistry
Bond (line) types indicate atom’s position with respect to the
plane of the paper…
- dashed: behind
- wedged: in front
- straight: in plane.
Drug structures drawn with only straight (or wiggly) bond lines
can be presumed to be racemic!
Mirror image plane
A and B are two
enantiomers

7. Thought question
Which (if any) atoms in each molecule is chiral?
How many stereoisomers (if any) can each molecule have?
Can things other then molecules be chiral or “handed”
How can you tell? Consider clothing, auto parts (mirrors, tires)

8. Thought question
Which (if any) atoms in each molecule is chiral?
How many stereoisomers (if any) can each molecule have?
Can things other then molecules be chiral or “handed”
How can you tell? Consider clothing, auto parts (mirrors, tires)

9. How does chirality come about?
• Biosynthesis – formation of a chiral center occurs
with preferential formation of only one enantiomer
(homochiral product)
• Chemical Synthesis – formation of a chiral center
usually leads to mixture of enantiomers (racemates)
H
H
Chemical
reaction
Enzymic
reaction

10. Compounds with >1 chiral center
• Can have a possible 2n stereoisomers
(N= no. of chiral carbons)
• Stereoisomers which are completely mirror
images are enantiomers
• Stereoisomers which are not completely
mirror images are diastereomers

11. Compounds with >1 chiral center (cont’d)
Stereoisomers that are not mirror images are diastereomers

12. Naming enantiomers:
• Need to be able to designate unambiguously
identity of individual enantiomers of a chiral
drug
• Two primary ways
– Polarized light rotation method
– Absolute configuration method

13. Naming enantiomers:
Polarized light
• Shine polarized light thorough solution of drug
in a polarimiter
• Purely empirical (experimental)
• Name enantiomers according to direction light
is turned
– To right –dextrorotatory (d) or (+)
– To left – levorotary (l) or (-)

14. Naming enantiomers:
Absolute Configuration
• Name enantiomers according to arbitrary
“Chain-Ingold-Prelog rules”
• Procedure FYI
– Assign priority to substituents 1 to 4, based on highest atomic
weight
– Orient molecule with #4 substituent in back of plane
– Draw a circular path for substituents 1 to 3
– If circle is in clockwise direction assign R config
– If circle is on counterclockwise direction assign S config
• Note: There is no relation between absolute configuration
(R, S) and polarized light rotation (d, l) !!!

15. Try it for yourself!
Click on the picture above to get instructions
FYI
Assigning absolute configurations

16. Biological interactions of
enantiomers
• Interaction with chiral agents, such as enzymes
and transporters are different
• Interactions with achiral probes, as in passing
through lipid bilayers of a cell, are the same
See accompanying video for demonstration!

17. http://www.ualberta.ca/~csps/JPPS
4(2)/R.Mehvar/Betablockers.pdf

18. Drug development: trend towards
single enantiomers
2004
Why this
trend?

19. “Chiral switching”
Development of active enantiomer of older racemic drugs

20. Test yourself…
Which of the following would interact differently
with the two enantiomers of a compound?
– Water (solubility)?
– Plane light (appearance under a microscope)?
– Polarized light (Optical rotation)?
– Heat (melting point)?
– Acid/base environment? (extent of ionization)?
– Metabolic enzymes (half-life)?
– Transport proteins (distribution)?
– Your tongue (taste)?

21. Test yourself…
Which of the following would interact differently
with the two enantiomers of a compound?
– Water (solubility)?
– Plane light (appearance under a microscope)?
– Polarized light (Optical rotation)?
– Heat (melting point)?
– Acid/base environment? (extent of ionization)?
– Metabolic enzymes (half-life)?
– Transport proteins (distribution)?
– Your tongue (taste)?

22. Flavor vs. structure
Spearmint Caraway
FYI

23. Test yourself
• How many chiral centers are present?
• How many stereoisomers are possible?
• How many stereoisomers are in the actual
drug product?
TimololPropranolol

24. Test yourself
• How many chiral centers are present?
• How many stereoisomers are possible?
• How many stereoisomers are in the actual
drug product?
TimololPropranolol