Stereochemistry and Drug Action

 Isomers and types of isomers

 Constitutional Isomers
• Functional Group Isomers
• Positional Isomers
• Geometric Isomers

 Stereoisomers
• Enantiomers
• Diastereomers
• Meso Compounds

 Conformational Isomers
• Eclipsed, gauche, staggered, syn-clinal, anti-clinal forms
• Chair, boat, pseudo-chair, skew-boat

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 Stereochemistry and Drug Action
 Functional Group Isomers
Same molecular formula, but different functional groups,
e.g., n-propanol and methyl ethyl ether
C H3 C H3

NH2 HN O

O
O O C H2C H3
3,4-M D A p h en acetin
(E cstasy) (analgesic)
 Positional Isomers
Same molecular formula, same functional groups, but different positions of
functional groups, e.g., n-propanol and i-propanol
Ph C O OEt Ph

C O O Et
N N
C H3 CH3
M e p irid in e
(A n a lg e s ic ) (n o t a n a lg e s ic )

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 Stereochemistry and Drug Action
 Geometric Isomers (cis/trans)
Same molecular formula, same functional groups, same positions, but different
orientation around a double bond or on a ring.

An important criteria to exhibit geometric isomerism is that the isomers cannot

be interconverted through mere rotation around a single bond.

OH HO

H H

H H

HO HO
tra n s -D E C c is -D E S
(E s tro g e n ic ) (n o n e s tro g e n ic )

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 Stereochemistry and Drug Action
 Geometric Isomers (cis/trans) … other examples

H3C N

Triprolidine (E)

Trans isomer, i.e., E, is 1000-times more histaminic than cis, Z

Me Me

OH

Me
Vitamin A has all E double bonds, any Z
would make it inactive!

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 Stereochemistry and Drug Action
 Stereoisomers

 Enantiomers …. pair of stereoisomers that are related to each other as non-super-

imposable mirror image isomers

 Meso compounds … stereoisomers that have more than one chiral center and are
super-imposable on their mirror images

 Diastereomers …. pair of stereoisomers containing more than one chiral center and are
not mirror images of each other

CH3 CH3 CH3 CH3

H Cl Cl H H Cl Cl H
Cl H H Cl H Cl Cl H
C2H5 C2H5 C2H5 C2H5
I II III IV

 What will be the effect of changing the –Et group to –Me?

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 Stereochemistry and Drug Action
 Stereo Isomers

 Enantiomers …. arise ….. four different substituents on a tetrahedral carbon

 ….. can also come about because of a tetrahedral nitrogen or phosphorus

 ….. may also arise due to bridge nitrogens/phosphorus

R4 O
+N Cl-
N
R3 R1 R3 R1
R2 R2

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 Stereochemistry and Drug Action

 Identify chiral centers (carbon, nitrogen, phosphorus)

OMe
MeO O O H3C
+ * N+
N O O * OMe
MeO
CH3

MeO
OMe
OMe
OMe
Atracurium besylate (neuromuscular blocking agent)

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 Stereochemistry and Drug Action
 Identify chiral centers (carbon, nitrogen, phosphorus)

N SCH3
N
H3C O
H3C N
N Nicotine N-oxide
O

Thioridazine N-oxide

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 Stereochemistry and Drug Action
 Identify chiral centers (carbon, nitrogen, phosphorus)

NH2 O O *
HO * *
OH CH3
*
N
HO HO * * *
OH Ph O
Nor-epinephrine warfarin
H3C
*
CH3 N
* quinine
H3C *
CH3
* * * HO
* H3C
*
HO 14R
cholesterol O 13S H 9R
5R
6S N
CH3
HO
morphine

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 Stereochemistry and Drug Action
 Enantiomers and projections

Ph D Ph
D
Standard Projection H3C H
H CH3
Even ‘D’ makes it different

H CH3 CH3
Saw Horse Projection Cl H H Cl
H3C Ph H Ph
D D
CH3
CH3 CH3
Cl H Cl H

Fischer Projection H Cl H Cl
C2H5 C2H5

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 Stereochemistry and Drug Action
 Identification of Enantiomers or Chiral Centers

 Step 1 identify chiral center

 Step 2 assign priority
… higher the atomic number, higher the priority
… atoms with same atomic number  heavier isotope, higher priority
… if same priority for immediate atoms, continue down the second atom
… double bonds are duplicated; triple bonds are triplicated
 Step 3 visualize molecule so that the group of lowest priority is directed away
 Step 4 draw (or visualize) Newmann projection of the remaining three groups
 Step 5 write the priority order 1, 2 and 3; draw (or visualize) an arrow traveling from 123
 Step 6 if the arrow travels clockwise, the chiral center is ‘R’; otherwise it is ‘S’

H H4 D3
‘R’
H3C Ph H3C2 Ph1 2 CH3 Ph 1
D D3

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 Stereochemistry and Drug Action
 Identification of Enantiomers or Chiral Centers

H H4 D3

‘R’
H3C Ph H3C2 Ph1 2 CH3 Ph 1
D D3
View from bottom

2 2
CH3 CH3 View from side CH3

4 ‘S’
H Ph H Ph1 Ph 1
D D3 3D

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 Stereochemistry and Drug Action
 Identification of Enantiomers or Chiral Centers

Ph Ph
D
Cl HO H H OH
Ph CH2CH2CH3 CH3NH H H NHCH3
C2H5 C2H5
(-)-ephedrine (+)-ephedrine
vasoconstrictor

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 Stereochemistry and Drug Action
 Properties of Enantiomers

 Physical properties … bp, mp, solubility, pKa, pKb, thermal stability, etc. …. all identical

 Rotate the plane of polarization of plane polarized light … the phenomenon of optical activity

Polarizer

Tube

Analyzer

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 Stereochemistry and Drug Action
 Properties of Enantiomers

 Reactivity with chiral molecules …. e.g., enzymes, receptors, ….. drug action/metabolism

Ph Ph Ph Ph
(R) HO H H OH (S) (S) H OH HO H (R)
(S) CH3NH H H NHCH3 (R) (S) CH3NH H H NHCH3 (R)
CH3 CH3 CH3 CH3
I II III IV
(-)-Ephedrine (+)-ephedrine (+)-pseudoephedrine (-)-pseudoephedrine
(vasoconstrictor)
36 11 7 1

(S) CH2Ph (R) CH2Ph

MeNH H H NHMe
CH3 CH3

I II
desoxyephedrine
Methamphetamine
10X more potent
CNS stimulant
Less cardiovascular

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 Stereochemistry and Drug Action
 Properties of Enantiomers

NH2 NH2
H N H3C N
O N O N
R S S S
H3C H
Ph CH3 Ph CH3

Cis-4-methylaminorex Effective dose

Potent amphetamine (5.5 mg/Kg) (>150 mg/Kg)
psychostimulant

H CH3 H
H3C
COOH HOOC

MeO OMe
S(+) R(-)
Naproxen

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 Stereochemistry and Drug Action

 Why do chiral molecules react differently with biological molecules?

A A A B

C B C A

A’ A’ A’ B’
C’ B’ C’ A’

R S

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