Stereochemistry of Drugs Intro

Question 1

What is a stereoisomer?

Answer 1

Molecules with the same molecular/structural formula but different arrangement of atoms in space

Question 2

What is a geometric isomer?

Answer 2

Arises from restricted rotation about double bonds

Question 3

Requirements for a stereoisomer/E/Z isomerism?

Answer 3

A double bond, and 2 different groups attached to either side of the C=C bond

Question 4

Describe isomer E

Answer 4

This is the trans isomer

The groups are furthest apart (diagonal)

Question 5

Describe isomer Z

Answer 5

This is the cis isomer

The groups are closer together (in line)

Question 6

CIP priority rules? (3)

Answer 6

1. Determine by atomic number of first atom
2. Compare subsequent atom if first atoms are the same
3. If there is a double or triple bond, duplicate the atoms

Question 7

What determines E/Z from CIP priority rules?

Answer 7

Z/cis = highest are on the same side

E/trans = highest are on opposite sides

Question 8

What is a chiral centre?

Answer 8

The middle group is attached to 4 different groups

Question 9

What is an enantiomer?

Answer 9

optical isomers (non-superimposable)

Only in chiral centres

There is a mirror plane

Question 10

What is R/S nomenclature/configuration?

Answer 10

After assigning CIP rules, number the 4 groups 1-4 and see if they number clockwise or anti-clockwise

S = Sinister = LEFT 
R = Rectus = RIGHT 

Enantiomer is mirror image of whichever configuration you have.

Question 11

How would you work out which enantiomer you have in a lab?

They have identical properties (melting/boiling point, density, infrared spectra, NMR…)

Answer 11

Test by direction of rotation of plane of polarised light using a POLARIMETER

If the compound rotates the plane or polarised light, it is optically active

For a pair of enantiomers the magnitude of rotation if identical but opposite directions

One rotates clockwise/DEXTROROTATORY

One rotates anti-clockwise/LAEVOROTATORY

Question 12

How to calculate specific rotation [a]

Answer 12

[a] = a / (c x l)

[a] = specific rotation
c = concentration of sample (g/ml)
l = path length of tube (dm)

Question 13

What is a racemic mixture?

Answer 13

An equal mixture of positive and negative enantiomers

Overall optically inactive mixture because the charges cancel out

Question 14

How many enantiomers in a molecule with 2 chiral centres?

Answer 14

4

Each chiral centre as 2 enantiomers (mirror images)

Question 15

What is a diastereoisomer?

Answer 15

Stereoisomers that are NOT enantiomers (not mirror images)

Question 16

What is a ‘meso’ compound?

Does this increase or decrease number of stereoisomers?

Answer 16

When there is a mirror plane within the structure itself

Decreases due to symmetry

Question 17

Formula to work out number of stereoisomers?

Answer 17

2^n

n = number of chiral centres

Question 18

Why do different stereoisomers have different biological activities?

Answer 18

Enantiomers of a drug will bind in different ways. One might bind more effectively/completely to a particular receptor than the other (higher affinity)

Therefore they might have different effects e.g. R/S carbone - different flavours and smells

Question 19

Discuss the considerations needed in development of drugs with chiral centres

Answer 19

They require much more data before clinical use approved

Must consider ADME, toxicity, trial results

Are both enantiomers active?
Do they have the same activity?
Is one more potent than the other?

Question 20

Trends in drug development?

Answer 20

Move to develop single enantiomers as they are ‘cleaner’

Racemic switch chemistry - existing racemic drugs can be redeveloped as single enantiomer drugs

More expensive/time consuming