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
MEDC 527 Fall 2008
1
Stereochemistry and Drug Action
 Functional Group Isomers
Same molecular formula, but different functional groups,
e.g., n-propanol and methyl ethyl ether
CH3
CH3
NH2
HN
O
O
OCH2CH3
O
3,4-MDA
(Ecstasy)
phenacetin
(analgesic)
 Positional Isomers
Same molecular formula, same functional groups, but different positions of
functional groups, e.g., n-propanol and i-propanol
Ph
COOEt
Ph
COOEt
N
N
CH3
Mepiridine
(Analgesic)
CH3
(not analgesic)
MEDC 527 Fall 2008
2
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
trans-DEC
(Estrogenic)
cis-DES
(non estrogenic)
MEDC 527 Fall 2008
3
Stereochemistry and Drug Action
 Geometric Isomers (cis/trans) … other examples
H3C
N
H
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!
MEDC 527 Fall 2008
4
Stereochemistry and Drug Action
 Stereoisomers
 Enantiomers …. pair of stereoisomers that are related to each other as non-superimposable 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
I
C2H5
II
C2H5
III
C2H5
IV
 What will be the effect of changing the –Et group to –Me?
MEDC 527 Fall 2008
5
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
Cl-
+N
R3
R1
R2
R3
N
R2
MEDC 527 Fall 2008
R1
6
Stereochemistry and Drug Action
 Identify chiral centers (carbon, nitrogen, phosphorus)
MeO
MeO
O
O
+ *
N
O
O
OMe
H3C
N+
*
OMe
CH3
MeO
OMe
OMe
OMe
Atracurium besylate (neuromuscular blocking agent)
MEDC 527 Fall 2008
7
Stereochemistry and Drug Action
 Identify chiral centers (carbon, nitrogen, phosphorus)
S
N
H3C
O
SCH3
N
N
N
H3C
O
Nicotine N-oxide
Thioridazine N-oxide
MEDC 527 Fall 2008
8
Stereochemistry and Drug Action
 Identify chiral centers (carbon, nitrogen, phosphorus)
*
HO
O
NH2
OH
OH
warfarin
Nor-epinephrine
CH3
*
H3C
*
HO
* * *
*
cholesterol
*
*
CH3
*
HO
H3C
O
Ph
HO *
O
*
N
* *
N
quinine
*
CH3
H3C
HO
14R
O
13S
H
5R
6S
HO
9R
N
CH3
morphine
MEDC 527 Fall 2008
9
Stereochemistry and Drug Action
 Enantiomers and projections
D
Standard Projection
H
H3 C
H
CH3
Even ‘D’ makes it different
H
Saw Horse Projection
Ph
D
Ph
H3C
D
CH3
CH3
H
Ph
D
Ph
Cl H
H Cl
CH3
CH3
CH3
Fischer Projection
Cl
H
H
Cl
C2H5
MEDC 527 Fall 2008

Cl
H
H
Cl
C2H5
10
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
H3C
D
D3
H4
Ph
H3C2
Ph1
D3
MEDC 527 Fall 2008
‘R’
2 CH3
Ph 1
11
Stereochemistry and Drug Action
 Identification of Enantiomers or Chiral Centers
H
H3C
D3
H4
D
Ph
H3C2
Ph1
D3
‘R’
2 CH3
Ph 1
View from bottom
2
CH3
H
D
Ph
4
H
CH3
View from side
Ph1
D3
MEDC 527 Fall 2008
2
CH3
‘S’
3D
Ph 1
12
Stereochemistry and Drug Action
 Identification of Enantiomers or Chiral Centers
D
Ph
Ph
Ph
Cl
CH2CH2CH3
HO
H
H
OH
CH3NH
H
H
NHCH3
C2H5
(-)-ephedrine
vasoconstrictor
MEDC 527 Fall 2008
C2H5
(+)-ephedrine
13
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
MEDC 527 Fall 2008
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Stereochemistry and Drug Action
 Properties of Enantiomers
 Reactivity with chiral molecules …. e.g., enzymes, receptors, ….. drug action/metabolism
Ph
Ph
HO
(R)
(S) CH3NH
(S)
H
H
OH
H
H
NHCH3 (R)
CH3
I
(-)-Ephedrine
(vasoconstrictor)
36
Ph
Ph
CH3
II
(+)-ephedrine
H
(S)
(S) CH3NH
H
CH3
III
(+)-pseudoephedrine
11
(S)
OH
7
CH2Ph
MeNH
H
CH3
I
HO
H
(R)
NHCH3 (R)
H
CH3
IV
(-)-pseudoephedrine
1
(R) CH2Ph
NHMe
H
CH3
II
desoxyephedrine
Methamphetamine
10X more potent
CNS stimulant
Less cardiovascular
MEDC 527 Fall 2008
15
Stereochemistry and Drug Action
 Properties of Enantiomers
NH2
NH2
O
N
O
N
R
S
S
S
Ph
Ph
CH3
CH3
H3C
N
H
H
H3C
Cis-4-methylaminorex
Potent amphetamine
psychostimulant
Effective dose
(5.5 mg/Kg)
H
CH3
COOH
H3C
N
(>150 mg/Kg)
H
HOOC
MeO
OMe
S(+)
Naproxen
R(-)
MEDC 527 Fall 2008
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Stereochemistry and Drug Action

Why do chiral molecules react differently with biological molecules?
B
C
A’
C’
A’
B’
B
A
A
A
C
A
A’
C’
B’
A’
R
S
MEDC 527 Fall 2008
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