RECOGNITION OF CHIRALITY
Chirality is the fundamental property of
3 –dimensional object.
Chiral chemistry was identified by Lowis pasteur
when in1948,for the first time seperated the 2-
isomers of sodium potassium tartarate.
• He found that the two isomers were identical in
physiochemical properties but different in their
ability to rotate plane polarized light.
WHY STUDYING STERIO CHEMICAL
FEATURES IS IMPORTANT
Biological Activity may reside in only one of the stereoisomer.
Stereoisomer's may show essentially similar qualitative And
Isomer may exhibit similar qualitatively but different quantitatively
Isomer may show distinct pharmacological activity.
• Property of a compound whose molecules are not super imposable
on their mirror images.
• Chirality = Handedness.
• Necessary condition for existence of enantiomers.
• Same molecular formula, same functional groups.
• Differ in the way atoms are oriented in 3 dimensions.
ASYMMETRIC CARBON ATOM
• Carbon atom to which 4 different atoms
or groups are attached.
The Two Types of Stereoisomers
Cis (on the same side) Trans (across/opposite sides)
Molecular Formula- C4H8
Molecular Formula- C4H8
Geometric Isomers and Drugs
Because geometric isomers have different chemical
and physical properties, they act differently as drugs in
our bodies as well.
•cis-platin used for chemotherapy - it can
enter cancer cells and interact with DNA
•Trans- platin - not active
have a chiral center
non-super imposable mirror
Optical Isomers Terminology
Chiral: if a molecule is chiral ( or displays chirality) this
means the molecule has two optical isomers
Chiral centre: the central carbon in an optical isomer with
four bonds each attached to a different group.
Enantiomer: another name for a molecule that is found in
optical isomers. For example, ibuprofen has a two
enantiomers, a left rotating enantiomer and a right
Racemic mixture: A mixture of 50% left rotating and 50%
right rotating optical isomers
• Stereoisomers that are mirror images of each other.
• Molecule and mirror image cannot be superimposed into each
other even after twisting and turning them.
• Identical physical and chemical properties
• Dextrorotatory ("+" / “d” form) - clockwise direction.
• Levorotatory ("-“ / “l” form) - anti-clockwise direction.
• Stereoisomers that are not mirror images of each other.
• Similar chemical properties but different physical
• Is an equimolar solution of the two enantiomers.
• Shows no optical rotation.
a = 1; b = 2 ; c = 3 ; d = 4
• Priority of an atom is determined
by its atomic number
• Order of substituents going from
highest to lowest priority.
• Clockwise – R (rectus).
• Anticlockwise – S (sinister).
• Unless established experimentally no idea whether (+) or (-)
rotation is associated with R or S configuration.
Arthur r. Cushny & “ChirAl”
1866 - 1926
• (-)-Hyoscyamine almost exactly twice as
active as atropine [( )- hysocyamine]
• (-)-Adrenaline twice the potency of ( )-adrenaline as a
vasoconstrictor (1908). (-)-enantiomer 12-15 fold more potent
than (+)-adrenaline on sympathetic vessels (1909).
• Biological Relations of Optically Isomeric Substances (1926).
Cushny & “ChirAl” phArmACology
Believed that the “receptor” was chiral and combined with the
enantiomers of the drug to produce diastereoisomeric drug –
“---- difference in action lies not in the facility with which the
chemical combination is formed, but in the physical
characteristics of the resultant compound” (Cushny, 1926).
• Affinity of a drug for a specific receptor and its intrinsic
activity are related to its chemical structure.
• Drug – receptor interactions are stereo selective.
• Minor changes in drug molecule structure.
• Major changes in pharmacological properties.
Why do we care about this subtle form of
Biomolecules (sugars, amino acids, DNA,
proteins, steroids) are chiral
– Proteins are built from L-amino acids, which implies
that enzymes – the catalysts of nature - are chiral
– Also, receptors (drug, taste, biopharmaceuticals,
agrochemicals) are chiral and the natural ligand to a
receptor is often only one specific enantiomer
– This is why mirror image molecules can have radically
different activities (effectivity, toxicity, taste) in the
Right-handed and left-handed molecules
interact with living systems in very different
ways and results for example in:
olfactory sensors are chiral
(R) Spearmint oil (S) caraway oil
• 57% marketed drugs were chiral.
• 2% single enantiomers.
• 80% drugs approved by the FDA were chiral.
• 75% single enantiomers.
CURRENT STATUS OF CHIRAL DRUGS
− In 2000, 40% of drugs on sale in the US were
− In 2004, about 80% of drugs entering market
are single enantiomer variants
− FDA now requires information about the
structure and activity of each isomer present
in a racemic mixture of a new medication.
What sparked the change????
• 1987 – change in FDA regulations.
• Inclusion of information on the enantiomer composition of
chiral compounds in new-drug applications.
• One asymmetric carbon atom, exists as 2 enantiomers
• S-Enantiomer → sedative
• R-Enantiomer Teratogen
• Unique metabolic pathway.
• Enzymatic or non-enzymatic.
• Involves unidirectional conversion of one enantiomeric
form to another.
R → S
• Development of a single enantiomer from a previously
• Resulted in a number of agents being re-marketed as
• Same or similar therapeutic indications.
• Novel indications for old compounds.
β2 ADreNErgic recePTOR AGONIST
• Salbutamol →Mixture of (R)-salbutamol and (S)-salbutamol
• Levosalbutamol is the (R)-enantiomer → active
Racemic and (S)-Salbutamol
• Induce airway hyper responsiveness.
• Increase sensitivity to allergen
• Inhalation of levosalbutamol→ greater bronchodilatation than the
equivalent dose of the racemate.
CALCIUM CHANNEL BLOCKER
• (S)-verapamil : vasodilating , cardiac antidepressant properties.
• (R)-verapamil : a vasodilating drug.
• Verapamil blocks the P170 glycoprotein.
• Interaction is non stereoselective.
• Partially reverse multiple drug resistance of cancer cells.
• R-verapamil might be expected to be more beneficial.
• S-Amlodipine → active calcium channel blocker.
• R-Amlodipine → inactive as calcium channel blocker.
• Mainly responsible for peripheral edema.
• Treatment of hypertension.
• S-Amlodipine is effective at half the
dose of racemate.
• Incidence of peripheral oedema is
• Treatment of normotensive angina patients.
• S-Amlodipine is effective at half the dose of racemate.
• Cardiotoxicity of the drug : R-enantiomer.
• Levobupivacaine - „S‟ enantiomer of Bupivacaine.
• Moderately more potent.
• Significantly reduced negative inotropic effect .
Levobupivacaine is less cardiotoxic.
SELECTIVE SEROTONIN REUPTAKE
• S-enantiomer of Citalopram.
• Doses that show improvement in depressed
10 mg / day – „S‟ enantiomer
40 mg / day – racemate
• Other advantages of Escitalopram.
• Faster onset of action.
• Reduction in side effects.
• Improved tolerability profile.
• Activity of racemic sibutramine – active metabolites.
• R-sibutramine metabolite are
More potent in the inhibition
of monoamine uptake.
Greater anorexic potency.
Under evaluation for treatment of depression.
Single enantiomer of metabolite - treatment of both obesity
• Inhibition of cyclooxygenase activity – „S’ enantiomer.
• 60% of R enantiomer undergoes chiral inversion to the
• chiral Dexibuprofen (1200 mg daily) was better than
racemate (2400 mg daily).
• Highly effective NSAID.
• Low adverse effect profile .
ADVANTAGES OF CHIRAL DRUGS
• Chiral drug is a single agent instead of a mixture of
two distinct drugs.
• Simplifies the interpretation of the Basic Pharmacology.
• Greater selectivity for their biological targets improved
therapeutic indices and reduced adverse effects.
• Longer or shorter duration of action - more appropriate
• Decreased inter individual variability.
SOME DRUGS ARE BETTER AS
• blockers currently used contain at
least one chiral center.
• Most are marketed as racemates.
• Two chiral centres ; four stereoisomeric forms.
• R, R-isomer : b -blocking property
• S, R-isomer : a -blocking property
• Remaining isomers : inactive
• Dilevalol ( R,R-isomer ) – elevated liver function tests.
• Chiral dilevalol was withdrawn.