outline (handout #3) a.importance of stereochemistry in...

1

Outline (Handout #3)

Stereochemistry in drug design

A. Importance of stereochemistry in drug design

B. Overview

C. Enantiomerism

D. Geometrical isomerism

E. Conformational isomerism

F. Possible pharmacological differences between stereoisomers

G. Review

A. Importance of stereochemistry in drug design and development

(a) Affecting drug pharmacological activity

(S)-(-)-thyroxinebiologically active

O CH2

CCO2H

HH2NI I

II

HO

(R)-(+)-thyroxineinactive

O CH2HO

I

I I

IC

CO2H

NH2

H

2

Fig. 2.18. (Foye�s) Optical isomers. Only in compound 6 do the functional groups A, B, and C align with the corresponding sites of binding on the asymmetric surface.

(b) Affecting drug (ligand) /receptor binding affinity

(R)-(�)-epinephrine

All three points of interaction with the receptor sites (required for receptor

activation):

1. A substituted aromatic ring with two hydroxyl groups

2. A â-hydroxyl group

3. A protonated secondary ammonium group

(S)-(+)-epinephrine

Only two interactions are provided

1. The protonated secondary ammonium and the substituted aromatic ring

2. The â-hydroxyl group occupies the wrong region of space and,

therefore, cannot interact properly with the receptor.

N-methyldopamine

Achieve the same interactions with the receptor as (S)-(+)-epinephrine

Its vasopressor response is the same as that of (S)-(+)-epinephrine and less

than that of (R)-(�)-epinephrine.

Fig. 2.19., Foye�s

3

Fig. 2.20. (Foye�s) Selective phases to which optical isomers may be subjected before biological response.

(c) Other mechanisms of enantiomer selectivity

All isomers

Constitutionalisomers

Diastereoisomers(diastereomers)

(Geometrical isomerism)Pairs of compounds that are

nonsuperimposable mirror images of each other

Enantiomers(Enantiomerism)

Pairs of compounds that are superimposable mirror

images of each other

Cis-trans isomers(Geometric isomers)

Other diastereoisomers (diastereomers)

(2 or more chiral carbons)

Configurational isomers

Conformationalisomers

B. Overview

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Constitutional isomers

Identical molecular formulae

Different linkage (bonds)

e.g. leu vs Ile

C

COOH

HH2N

CH2

CH3

HC CH3

Ile Leu

C

COOH

HH2N

CH2

CHH3C CH3

Conformational isomers


Conformational differences due to flexible single bonds

HH3C

OH H

HO

C CCH3

HH3C

OHOH

H3C

C CH



Same bonds

Different shape

Structurally rigid groups

Cannot be interconverted without breaking bonds

e.g.


(Geometrical isomerism)Pairs of compounds that are

nonsuperimposable mirror images of each other


Pairs of compounds that are superimposable mirror

images of each other





HH3C

OHH

HO

C CCH3 H

OH H

HO

C CCH3

H3C

DiethylstilbesterolC2H5

HOC2H5

OHC2H5

C2H5

OHHO

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C. Enantiomerism (Pairs of compounds that are superimposable

mirror images of each other)

(a) Mirror plane and chiral center

C

CH3

CH2CH3HHO

CH

OH

CH3

CH3CH

2

(S)-2-butanol(R)-2-butanol

Practice problem #1:Identify the chiral carbons in the following structures

CH3CHCH2CH2CH3

Cl

CH3CCH2CH3

CH3

Cl

BrH

Br H

H H

BrBr

(b) CIP (Cahn-Ingold-Prelog) convention

(R and S nomenclature) Priority of groups attached to the chiral center

Atomic number (not atomic weight) in the periodic table

I>S>O>N>13C>12C>Li>3H>2H>1H

In case of ties of the first atoms, use the next atoms

along the chain as tiebreakers

For double and triple bonds, both atoms in the bond will

be duplicated or triplicated

CCH

3

CH2CH

2Br

H

CH(CH3)

2

CH2

CH(CH3)2 > CH2CH2Br > CH3CH2

C Y C Y

Y C

C Y C Y

Y C

C

Y

C

CH CH

2OH

OH

O

C O

HC

C

O

H CH 2OHOH

H

6

In a 3-D drawing model, put the 4th (least) priority group and its bond to

the chiral carbon in back.

Then look at the positions of the other three groups and draw an arrow

from the 1st priority group to the 2nd group to the 3rd group

Clockwise arrow (R, for Rectus in Latin, right) configuration

Counterclockwise arrow (S, for Sinister, left) configuration

Cahn-Ingold-Prelog convention (Continued)

Practice problems:

1. Identify the asymmetric carbon and

determine the (R) or (S) isomers

CH3C

OH

COOHH CH3C

COOH

H

OHCH

H3C

OH

CH2

CH3C H

CH3

OH

H2CH3C

CH3CH

OH

CH2

CH3

2-butanol

Practice problem #2: Draw a 3-dimensional formula for (R)-2-chloropentane

1: Identify the chiral carbon.

2: Determine the priority of each group

attached to the chiral carbon.CH3 C CH2CH2CH3

Cl

H

*

3: Redraw a molecule with the chiral carbon in

the center and the lowest priority group attached

to the �dashed� wedge (pointing away from you).

CH

4: Place the highest priority group at the top of

the molecule.

5: Clockwise (4 3 2) R configuration (Count-

clockwise (4 3 2) S configuration)

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(c). Fisher projections

All horizontal bonds project toward you

All vertical bonds project away from you.

Therefore, a Fischer projection cannot be rotated by

90° or 270° in the plane of the screen.

Vertical (lowest priority group), Clockwise = R (VCR)

Horizontal (lowest priority group), Clockwise = S (HCS)

Vertical, Counterclockwise = S

Horizontal, Counterclockwise = R

Fig. 2.17. (Foye�s) Relationship of optical isomers of serine to D- and L-glyceraldehyde

CHO

CH2OH

OHHH

OH

CHOCH2OH

CH2OH

CHO

HO H

H

OH

CHOCH2OH

90°

CHO

CH2OH

OHH270°

CH2OH

CHO

HO H

1

432

4

321

4

312 1

342

1

423

1

234

4

132

4

213



Vertical, Counterclockwise = S Horizontal, Counterclockwise = R

Practice problem #3 Fisher projections

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D-glucose (2-(R)-3-(S)-4-(R)-5-(R)-6-

pentahydroxyhexanal, hexanal for the aldehyde group)

Nomenclature: Highest numbered chiral center

Practice problem #4:

Draw the Fischer projection of 2-(R)-

3-(S)-4-(R)-5-tetrahydroxylpentanal

(d). D-glucose and D-/L- isomers



Vertical, Counterclockwise = S Horizontal, Counterclockwise = R

(e) Cyclization of aldohexoses

D-glucose (2-(R)-3-(S)-4-(R)-5-(R)-6-

pentahydroxyhexanal, hexanal for the

aldehyde group) HOHO

O

HO

HOOH

HOHO

O

HO

HO

OH

HO

H

OH

H

OH

OH

H

OH

H O

H

HO

OH

H

H

OH

OH

H

OH

H O

H

Anomers

One of two stereoisomers of

cyclic saccharide that differ only in

its configuration at the hemiacetal or

hemiketal carbon (anomeric carbon)

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(f). Optical Activity

(1). Polarimetry (Definition):

Experimental technique used to distinguish between

enantiomers by measuring the interaction between

enantiomers and plane polarized light.

(2). Polarimetry and calculations

Unpolarized lights (usually by the sodium vapor lamp)

589.3 nm (Sodium D line)

Unpolarized light vibrates in all directions

Plane-polarized light

Light vibrates in only a single plane by passing

through a polarizing filter

Measurement of the optical properties of chiral

compounds

When plane polarized light passes through a

solution containing a single chiral compound, the

chiral compound causes the plane of vibration to

rotate.

The direction and magnitude of rotation must be

determined experimentally.

There is no correlation between (R) and (S)

configuration and the direction of rotation.

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Light sourcePolarizer

Plane polarized light

Sample tube

Analyzer

Results

(3). Instrument and mechanism

(4). Quantitative measurement

[á] = áObserved/(c × l)

l=length of sample tube in decimeters (=10cm)

c=conc. of sample in w/v

áObserved= Obsreved á value

Dextrorotatory (clockwise, to the right, or + IUPAC

convention)

Laevorotatory (anticlockwise, to the left, or -, IUPAC

convention)

Racemic mixture

For example:

C

CH3

CH2CH3HHO

CH

OH

CH3

CH3CH

2

(S)-2-butanol (R)-2-butanol

+13.5o rotation -13.5o rotation

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(5). Practice problem #4

A solution of 2.0 g of (+)-glyceraldehyde in 10.0 mL of water

was placed in a 100.0 mm polarimeter tube. Using the sodium

D line, a rotation of 1.74o was observed at 25oC. Calculate the

specific rotation of (+)-glyceraldehyde.

L (length of sample tube in decimeters or dm) = ?

c (conc. of sample in w/v) = ?

[á] = á/(c × l) = ?

Practice problem #5

The rotation of (S)-2-butanol is 13.5o and (R)-2-butanol is-13.5o. The

rotation of a mixture of (S)-2-butanol and (R)-2-butanol is -6.75. What is

the percentages of each enantiomer in the mixture?

X represents the percentage of (S)-2-butanol:

X (13.5) + (1-X)(-13.5) = -6.75

13.5X + (-13.5) � (-13.5X) =-6.75

27X =-6.75 � (-13.5)

X=?

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D. Geometrical isomerism

(Pairs of compounds that are nonsuperimposable mirror images of

each other)

(1). Overview Diastereoisomers(diastereomers)

(Geometrical isomerism)




Many molecules have asymmetric carbons but are identical to its mirror image and have internal mirror plane of symmetryi.e., Cis-1,2-dichlorocyclopentane

H H

ClCl

H H

ClCl

H H

ClCl

Practice problem #6: Which of the following compounds contain an internal mirror plane of symmetry?

C

H

ClHFF F

HH

C C

CO2H

HOH

HHO

HO2C

C C

CO2H

OHH

HHO

HO2C

C CBr

BrH

HCH3CH2

CH2CH3

CH3H

H3C H

BrH

Br H H H

BrBrCH3CCH2CH3

CH3

ClCH3CHCH2CH2CH3

Cl

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(2).Cis-trans isomers

Restricted bond rotation by carbon-carbon double bonds

With 2-butene, when the methyl groups are on the same side,

the molecule is defined as the cis- or Z-isomer (from the

German zusammen, meaning �together�);

When they are on opposite sides, the designation is trans- or

E- (from the German entgegen, meaning �opposite�).

CH3

ClH3

CH3 CH3

Practice problem #7

Which one is a cis isomer and which one is a trans isomer?

Cl

Cl

Cl Cl Cl

Cl

Cl Cl

Cl

Cl

Cl Cl Cl

Cl

Cl Cl

Restricted bond rotation by cyclic structures

H

H3C

H

H3C

H

H3C

H

H3C

Practice problem #8


HHO

H3C

OO

CH3

OHH

H

HHO

H3C

OO

CH3

OHH

H

Fig. 2.25. The 5á and 5â conformations of the

steroid nucleus cholestane.

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Other types of cis-trans isomers

Figure 2.13 (From Wilson and Givold�s) Examples of E- and Z-isomers.

(a)

C2H5

HOC2H5

OH

C2H5

C2H5

OHHO

H3C CH3 H3C CH3

(b)

(c)(d)

Practice problem #9


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O

H3C O

Extended acetylcholine

O

H3C O

Skewed acetylcholine

N

Nicotine

O

HO

Muscarine

Endogenous (Acetylcholine) Exogenous

Nicot

ine

rece

ptor

Mus

carinic

rece

ptor

N+N+

N+

N+

E. Conformational isomers


Mirror structures due to flexible single bonds Conformational isomers and ligand specificity

Acetylcholine receptor agonists

Nicotinic receptors vs muscarinic receptors

Nicotinic receptor Muscrinic receptor

Acetylcholine

Specific agonist

Antagonist

Receptor structure

Transduction mechanism

TubocurarineHexamethonium

Atropine

Ligand-gated ion channels(5 subunits) GPCR

Ligand-controlled opening of ion channels

G-protein related signal transduction cascade

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F. Possible pharmacological differences between stereoisomers

Both isomers are active with the same pharmacological

effect and potency

Both isomers are active with the same pharmacological

effect but their potencies are different

Both are active but with different pharmacological effects

One is active and the other is inactive

Both are active but with different side effects

Example 1 Both isomers are active with the same

pharmacological effect and potency

Chloroquine

Antimalarial drug

Both R and S isomers have equal activities

NH

H3C CH

CH2

CH2

CH2

NCH2 CH2 CH3H3C

Cl N

Example 2 Both isomers are active with the same

pharmacological effect but their potencies

are different

Diethylstilbesterol

An estrogen agonist

The E isomer is 7% as active as the Z

isomer

C2H5

HOC2H5

OH

C2H5

C2H5

OHHO

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Example 3 Both are active but with different

pharmacological effects

Ketamine

The S-isomer is an anesthetic

The R-isomer is a psychotic

ONHCH3

Cl

Example 4 One is active and the other is inactive

Methyldopa

The S-isomer is a hypertensive drug

The R-isomer is not active

HO

HO CH2 C

COOH

NH2

CH3

Example 5 Both are active but with different side effects

Thalidomide

The S-isomer is a sedative with teratogenic side

effects

The R-isomer is also active but with little teratogenic

activity

O

O

N

H

NH

O

O

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G. Review

(a). Stereoisomers or not stereoisomers?

They are isomers

They are not isomers

Two compounds

Q1: Share the same molecular formulae?

NoYes

Constitutional isomersi.e., Leucine vs. isoleucine

Q2: Share the same connectivity?

NoYes

Stereoisomers

(b). Conformational vs. configurational

Configurational

Conformational

Two stereoisomers

Q1: Are they interconvertable by rotation of single bonds?

Yes

No

Optical

Q2: Does the isomerism occurs at a double bond or other rigid structures?

NoYes

Geometric

H3C

CH3

HH

HH

CH3

HHHH

CH3

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(c). Diasteromers vs. enantiomers

Isomers with different optical properties

Are they non-superimposable mirror images?

Diastereomers

NoYes

Enantiomers

CH3CH2

Cl

HCH3

Cl

CH2CH3H3CH

H3C

H3C

ClH

HBr

H3C

H3C

HCl

HBr

(d). Comparasion

Enantiomers

Nonsuperimposable

But mirror-imaging

Diastereomers

Nonsuperimposable

Nonmirror-imaging


(Geometrical isomerism)


Stereoisomers

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