kimia medisinal i

Kimia Medisinal I(2 SKS)

P6: Hubungan stereokimia dan aktivitas obat

Genap | 2021

Sifat kimia fisika sbg dasar aktivitas obat

Pada proses absorpsi dan distribusi obat

dipengaruhi oleh: sifat lipofilik molekul obat (kelarutan

dalam lemak/air) dan sifat elektronik molekul obat

(derajat ionisasi, suasana pH)

Pada proses interaksi obat dan reseptor

dipengaruhi oleh: tipe ikatan kimia, interaksi hidrofobik, kerapatan elektron, ukuran molekul obat, dan efek

stereokimia sifat sterik dan elektrik molekul obat

Dari kuliah sebelumnya...

Hadi | Kimia Medisinal I | 2021 2

Structure-physiochemical properties:

Water solubility, partition coefficient, …

Stereochemistry biomolecules (reseptors,

enzymes)


Importance:

In pharmaceutical industries, 56% of the drugs currently

in use are chiral molecules and 88% of the last ones are

marketed as racemates (or racemic mixtures), consisting

of an equimolar mixture of two enantiomers.


Thalidomide cases

In 1960 in Europe, racemic

thalidomide was given to

pregnant females to cure

morning sickness.

This led to deformations in

babies and neurotoxic effects.

These were due to S-

thalidomide.

R-thalidomide contained the

desired therapeutic activity


Example:

In biological system there is a preference of a specific

stereoisomer.

Amino acids: 20 amino acids (exc. glycine) have L-

and D- forms, only the L- form is proteogenic


Example:

Sugars: most sugars (e.g. glucose, fructose) occur

naturally as the D-form


D and L chirality

Dextrorotary compound: "(+)-" or "d-"

Levorotary compound: "(−)-" or "l-"


Isomers:


Example: constitutional isomers

Functional group: Same molecular formula, but

different functional groups,

e.g., n-propanol and methyl

ethyl ether

Positional:Same molecular formula,

same functional groups, but

different positions of

functional groups, e.g., n-

propanol, 2-propanol

O

O

CH3

NH2

NH

CH3

O

OCH2CH

3

3,4-MDA phenacetin

(Ecstasy) (analgesic)

N

CH3

Ph COOEt

N

CH3

Ph

COOEt

Mepiridine

(Analgesic) (not analgesic)


Example: configurational isomers

Geometric (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.

H

H

OH

OH

H

H

OH

OH

trans-DEC cis-DES

(Estrogenic) (non estrogenic)

H

N

NCH3

Triprolidine (E)

Trans isomer, i.e., E, is 1000-times more

histaminic than cis, Z


Stereoisomers

Enantiomers: pair of

stereoisomers that are related

to each other as non-super-

imposable mirror image

isomers

Diastereomers: pair of

stereoisomers containing more

than one chiral center and are

not mirror images of each

other


Enantiomers: non-superimposible mirror images

mirror plane

Lactic acid

from muscle tissue

Lactic acid

from milk

R = Rectus

S = Sinister


Diastereomers: stereoisomers that are not mirror

images

L-erythrose L-threose

has the R configuration at

C2 and the S configuration

at C3

has both S configuration

at C2 and C3


Chiral center

Chiral molecules usually contain at least

one carbon atom with four non-identical

substituents.


Identification of chiral centers

Chiral centers: carbon, nitrogen, phosphorus

N

CH3

O

O

O

O

NCH

3

OMe

OMe

OMe

MeOOMe

OMe

MeO

MeO

Atracurium besylate (neuromuscular blocking agent)

++

**



Chiral centers: carbon, nitrogen, phosphorus

OH

OH

OH

NH2

Nor-epinephrine

O O

OH

CH3

OPh

warfarin

N

NOH

quinine

*

*

* * *

*

*

CH3

CH3

CH3

OH

CH3

CH3

cholesterol

*

**

***

**

O

N

H

OHCH

3

OH

9R

6S

5R

13S

14R

morphine



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

123: if the arrow travels clockwise, the chiral center is ‘R’; otherwise it is

‘S’

CH3

H

DPh

D

PhCH3CH

3

H

DPh12

3

4

12

3

‘R’


CH3

H

DPh

D

PhCH3CH

3

H

DPh12

3

4

12

3

‘R’

View from bottom

H

CH3

DPh

D Ph

CH3

H

CH3

DPh1

2

3

4

1

2

3

‘S’

View from side


Polarizer

Tube

Analyzer

Polarizer

Tube

Analyzer

Properties of enantiomers

Physical properties (bp, mp, solubility, pKa, pKb, thermal

stability, etc..) all identical

Rotate the plane of polarization of plane polarized light

optical activity


Properties of enantiomers

Why do chiral molecules react differently with biological

molecules?

R S

A A A B

C B C A

A’ A’ A’ B’

C’ B’ C’ A’


Different enantiomers behaviour

Absorption (membrane selectivity)

Metabolism

Binding to other reseptors than target (loss, side

effects)

Binding to target reseptor


Importance of stereochemistry

Efficacy, adverse effects, and toxicity of drugs may be

enantiospecific

Example 1: Atorvastatin, fluvastatin, and rosuvastatin

(anti-hypercholesterolemia) exist in four optical forms, but they are currently used as enantiopure drugs, i.e.,

only one single enantiomer.


CH3

HOH

HCH3NH

Ph

CH3

OHH

NHCH3

H

Ph

(-)-Ephedrine (+)-ephedrine (+)-pseudoephedrine (-)-pseudoephedrine

(vasoconstrictor)

36 11 7 1

(R)

(R)

(S)

(S)

I II

CH3

OHH

HCH3NH

Ph

CH3

HOH

NHCH3

H

Ph

(S)

(R)

(R)

(S)

III IV

CH2Ph

CH3

HMeNH

CH2Ph

CH3

NHMeH

I II

(R)(S)

Methamphetamine

10X more potent

CNS stimulant

Less cardiovascular

desoxyephedrine


Example 2: Ephedrine


O N

CH3

NH2

Ph

O N

CH3

NH2

Ph

Cis-4-methylaminorex

Potent amphetamine

psychostimulant

R S S S

NH

CH3

NCH3

H

Effective dose

(5.5 mg/Kg) (>150 mg/Kg)

H CH3

COOH

MeO

CH3

H

OMe

HOOC

S(+) R(-)

Naproxen


Example 3:


Channel blockers

Calcium channel blockers prevent calcium from entering

cells of the heart and blood vessel walls, resulting in

lower blood pressure.

Example 1: Diltiazem and verapamil are both chiral,

possessing asymmetric centers. In each case, the

dextro-rotatory (i.e. the (+)-enantiomer) is approximately

10 times more potent as a calcium channel blocker than

the levo-rotatory (i.e. (–)-enantiomer ).


Example 2: Amlodipine is used therapeutically as a

racemic mixture, composed of S- and R-enantiomers,

but its calcium channel-blocking effect is confined to S-

amlodipine; R-amlodipine has 1000-fold less activity than

its S-enantiomer. The affinity of its levorotary (-)-

enantiomer to the calcium channels is 1,000 times

superior to that of its dextrorotary (+)-enantiomer.


Receptors/enzymes

The biological receptors (including enzymes) for drugs are

chiral they respond to only one isomer of a ligand/drug.

The isomer with desired biological activity is called eutomer

and the other isomers are called distomer.


Receptors/enzymes

There is an enzyme with three

binding site for an amino acid.

If the amino acid was in a non-

enzymatic reaction, the

stereochemistry is selected by bulky

groups’ positions and we will get all

the stereoisomers even though one

isomer will be preferred.

But in an enzymatic reaction, the

amino acid has to bind with the

specific binding site before catalysis.

Thus enzymatic reaction is always

stereoisomer specific.


other isomers of the molecule may be catalysed by the

enzyme if the enzyme has additional binding site, but

even then the catalysis is usually weak.

the binding specificity of a chiral receptor site for a chiral

molecule is usually only favorable in one way The

biological receptors (including enzymes) for drugs are

chiral. Therefore they respond to only one isomer of a

ligand/drug.


Anaesthesia

More than half of the synthetic agents used in anaesthesia practice are chiral drugs.

Almost all are administered as racemic mixture, rather

than as single pure enantiomers.

Examples:

- inhalational general anaesthetics (e.g. isoflurane),

- intravenous anaesthetics (e.g. etomidate, thiopentone),

- neuromuscular blocking agents (e.g. cisatracurium)

- local anaesthetics (e.g. ropivacaine and levobupivacaine)


Etomidate

Administered as a single

isomer: R-isomer

Site of action: GABAA

receptor.

R-isomer is 15 times more

potent than the S-isomer.

S-isomer lacks hypnotic

activity.

etomidate


Ketamin

S-ketamine is 2-4 times more

potent than R-ketamine as an

anaesthetic and analgesic agent.

R-ketamine: emerge reactions like

hallucinations, vivid dreams and

agitation

Metabolism of S-ketamine by liver

microsomes is 20% greater than R-

ketamine and 10% greater than the

racemate, faster clearance of the

drug.

ketamin


Isoflurane

S(+)-isoflurane reported to be

50% more potent than R(-)-

isoflurane

Both enantiomers are equally

soluble in the lipid bilayers.

S-isoflurane induced about 50%

longer sleep times than R-

isoflurane

Majority of the inhalational

agents currently used are chiral

except, sevoflurane


isoflurane

Other anaesthesia

other agents (e.g. levosimendan, dexmedetomidine,

L-cysteine).

levosimendan dexmedetomidine


Adrenaline

The (-) enantiomers exert stronger effect i.e; heart

rate increases

X-ray crystallography of adrenaline Enantiomers shown

that negative form has R configuration and the positive

form has S configuration


Neuromuscular blocking agents:

atracurium

Intermediate duration non-depolarizing neuromuscular

blocker.

Causes histamine release, transient hypotension,

tachycardia, facial or truncal flushing.

Contains 4 chiral centres and is a mixture of 10 optical and

geometric isomers.


atracurium

Potential advantages of single

enantiomer products

Less complex, more selective pharmacodynamic

profile

Potential for an improved therapeutic index

Less complex pharmacokinetic profile

Reduced potential for complex drug interactions

Less complex relationship bebetween plasma

concentration and effect


Absorption and stereoselectivity

For the majority of racemic drugs, absorption

appears to be by passive diffusion, provided no

stereoselectivity.


Carrier mediated transporter

Stereo selective

intestinal transporter is the

main cause for marked

differences in the oral

absorption of enantiomers.

L-Methotrexate have 40

fold higher Cmax and AUC

than D-Methotrexate.


methotrexate

Distribution

Stereo selective plasma protein binding could

influence distribution and elimination because

the major determinant of drug distribution and elimination is protein binding.

The enantiomers may display different

magnitudes of stereoselectivity between the

various proteins found in plasma


Example:

R-propranolol binding to

albumin is greater than S-

propranolol and the opposite is

observed for 1–acid

glycoprotein (AAG)

R-propranolol: highly albumin

bound, less potent

S-propranolol: highly bound to

AAG, available as unbound,

40-100 time more potent


propranolol

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