Stereochemistry is the ‘chemistry of space’ , that is stereochemistry deals with the spatial arrangements of atoms and groups in a molecule.
Stereochemistry can trace its roots to the year 1842 when the French chemist Louis Pasteur made an observation that the salts of tartaric acid collected from a wine production vessel have the ability to rotate plane-polarized light, whereas the same salts from different sources did not have this ability.
Isomers are compounds that contain exactly the same number of atoms, i.e., they have exactly the same empirical formula, but differ from each other by the way in which the atoms are arranged.
Constitutional isomers, also known as structural isomers, are specific types of isomers that share the same molecular formula but have different bonding atomic organization and bonding patterns.
Stereoisomers are molecules having the same molecular formula and the atomic arrangement, but differ in their spatial arrangement.
Geometric isomers are two or more coordination compounds which contain the same number and types of atoms, and bonds (i.e., the connectivity between atoms is the same), but which have different spatial arrangements of the atoms.
There are 2 types of geometric isomers, ‘cis’ and ‘trans’.-cis isomers: when similar groups are present on the same side of the double bonds, then they are termed as cis.- trans isomers: when similar groups are present on the opposite sides of the double bonds then they are called trans isomers.
cis-diethylstilbestrol has only 7% of the estrogenic activity of trans-diethylstilbesterol.
Cisplatin have anticancer activity where ae trans platin is an inactive compound.
In chemistry, a molecule or ion is called chiral if it cannot be superposed on its mirror image by any combination of rotations, translations, and some conformational changes.
Chirality is the property of being non identical to ones mirror image.
Chiral center is defined as the atom bearing 4 different atoms or group of atoms.
Molecules that form nonsuperimposable mirror images, and thus exist as enantiomers, are said to be chiral molecules.
For a molecule to be chiral, it cannot contain a plane of symmetry.
The term enantioselectivity refers to the efficiency with which the reaction produces one enantiomer.
Enantiomers are stereoisomers that are non-superimposable mirror images.
Have identical properties.
Similar shapes
Diastereomers are stereoisomers that are non superimposable and are not mirror images.
Have distinct physical properties.
Have different molecular shapes.
Enantiomers consist of a pair of molecules that are mirror images of each other and are not superimposable.
When a molecule contains only one chiral centre , the two stereoisomers are known as enantiomers.
These may be referred to or labelled using the configurational descriptors as either:
R(rectus meaning right handed) or S(sinister meaning left handed),
D(dextrorotatory)or L (laevorotatory)
E-Entgegen or Z- Zusamen
1. PRESENTED BY:
ACHAL YAWALKAR
M.PHARM I YEAR
PHARMACEUTICAL CHEMISTRY
GUIDED BY:
Dr. B.R. PRASHANTHA KUMAR
ASSOCIATE PROFESSOR
DEPT OF PHARMACEUTICAL CHEMISTRY
2. Elements
1. WHAT ARE ISOMERS ?
2. WHAT ARE STEREOISOMERS ?
3. WHAT IS CHIRALITY ?
4. WHAT DO YOU UNDERSTAND BY
THE TERM ENATIOSELECTIVITY &
HOW IS IT RELATED TO VARIOUS
PHARMACOKINETIC PARAMETERS
?
3. STEREOCHEMISTRY
Stereochemistry is the branch of chemistry that involves “the study of the different spatial arrangements of
atoms in molecules”.
Stereochemistry is the ‘chemistry of space’ , that is
stereochemistry deals with the spatial arrangements of atoms
and groups in a molecule.
Stereochemistry can trace its roots to the year 1842 when
the French chemist Louis Pasteur made an observation that
the salts of tartaric acid collected from a wine production vessel
have the ability to rotate plane-polarized light, whereas the
same salts from different sources did not have this ability.
4. ISOMERS:
Stereoisomers are molecules having the
same molecular formula and the atomic
arrangement, but differ in their spatial
arrangement.
Isomers are compounds that contain exactly the
same number of atoms, i.e., they have exactly
the same empirical formula, but differ from each
other by the way in which the atoms are
arranged.
STEREOISOMERS:
Constitutional isomers, also known as
structural isomers, are specific types of
isomers that share the same molecular
formula but have different bonding atomic
organization and bonding patterns.
CONSTITUTIONAL
ISOMERS:
5. GEOMETRIC ISOMERS:
Geometric isomers are two or more coordination compounds which contain
the same number and types of atoms, and bonds (i.e., the connectivity
between atoms is the same), but which have different spatial arrangements
of the atoms.
There are 2 types of geometric isomers, ‘cis’ and ‘trans’.
-cis isomers: when similar groups are present on the same side of the
double bonds, then they are termed as cis.
- trans isomers: when similar groups are present on the opposite sides
of the double bonds then they are called trans isomers.
cis-diethylstilbestrol has only 7% of the estrogenic activity of trans-
diethylstilbesterol.
Cisplatin have anticancer activity where ae trans platin is an inactive
compound.
6. In chemistry, a molecule or ion is called chiral if it cannot be superposed on its mirror image by any
combination of rotations, translations, and some conformational changes.
Chirality is the property of being non identical to ones mirror image.
CHIRALITY:
Chiral center is defined as the atom bearing 4 different atoms or group of atoms.
Molecules that form nonsuperimposable mirror images, and thus exist
as enantiomers, are said to be chiral molecules.
For a molecule to be chiral, it cannot contain a plane of symmetry.
A plane of symmetry is a plane that bisects an
object (a molecule, in this case) in such a way
that the two halves are identical mirror images.
7. ENATIOSELECTIVITY:
The term enantioselectivity refers to the efficiency with which the reaction produces one
enantiomer.
ENANTIOMERS DIASTEREOMERS
Enantiomers are stereoisomers
that are non-superimposable
mirror images.
Have identical properties.
Similar shapes
Diastereomers are stereoisomers that
are non superimposable and are not
mirror images.
Have distinct physical properties.
Have different molecular shapes.
8.
9. ENANTIOMERS
Enantiomers consist of a pair of molecules that are mirror images of each
other and are not superimposable.
When a molecule contains only one chiral centre , the two stereoisomers are
known as enantiomers.
These may be referred to or labelled using the configurational descriptors as
either:
R(rectus meaning right handed) or S(sinister meaning left handed),
D(dextrorotatory)or L (laevorotatory)
E-Entgegen (high priority groups on opposite side of double bond) or Z-
Zusamen (high priority groups on
same side of double bond)
10. The most famous example of a chiral drug is Thalidomide.
Thalidomide has a tragic history :
It was introduced in Germany in 1957 as a sedative and hypnotic and was marketed over the
counter largely as a drug for treating morning sickness in pregnant women.
In the following few years, about 10,000 infants worldwide were born with phocomelia, or limb
malformation. Only half of the infants survived, and some of those who did had other defects in
addition to limb deficiencies.
Thalidomide exists in two mirror-image forms: it is a racemic mixture of (R)- and (S)-enantiomers. The (R)-
enantiomer, shown in the figure, has sedative effects, whereas the (S)-isomer is teratogenic. Under
biological conditions, the isomers interconvert, so separating the isomers before use is ineffective.
The thalidomide disaster caused many
countries to tighten drug approval regulations.
11. Vigabatrin, one of the most widely used
antiepileptic drugs, is marketed and administered
as a racemic mixture in which only S-enantiomer is
therapeutically effective.
R- Vigabatrin
S-Vigabatrin
Tramadol is marketed as a racemic mixture of both R- and S-
stereoisomers, because the two isomers complement each other's
analgesic activities .
The (+)-isomer is predominantly active as an opiate with a higher
affinity for the µ-opiate receptor (20 times higher affinity than the (-)-
isomer).
12. PHARMACOKINETIC PARAMETERS:
1.Absorption
Passive intestinal absorption
Carrier transporter stereoselectivity
Oral bioavailability
Local blood flow
2. Distribution
Protein binding
Tissue distribution
Storage mechanism
Tissue uptake transporter
Efflux process
3.Metabolism
First pass metabolism
Phase 1 and Phase 2 metabolism
4. Elimination
Glomerular Filtration
Active secretion
Passive & active reabsorption.
13. The process of movement of drug from its site of administration to systemic circulation is
called as absorption.
Most important mechanism of drug absorption is passive diffusion through biological
membranes, a process that is dependent upon the physicochemical properties of the
molecule:
i. Lipid solubility
ii. pKa
iii. Molecular size
iv. Dissloution time
v. Drug stability …..etc
If a chiral drug is absorbed by a passive process then differences between enantiomers
would not be expected.
In contrast , diastereoisomers may show differences in absorption as a result of the
differences in their solubility i.e
Enantiomeric
Do not show any differences in the absorption rate
Diastereomeric
May show differences in absorption as a result of the
differences in their solubility.
14. The aqueous solubility of ampicillin with 2R stereochemistry in
the acylated side chain (corresponding to D- configuration) is
greater than that of 2S epimer (L-configuration in side chain).
Many of the b-lactam antibiotics are substrates for the gut dipeptide
transport system and as such their absorption would be expected to be
stereoselective.
The influence of the stereochemistry of the 7-acyl side chain on the
absorption of the diastereoisomers of cefalexin has been
investigated in the rat.
Both diastereoisomers are substrates for the carrier-mediated
transport system with the L-epimer showing a higher affinity than,
and acting as a competitive inhibitor for, D-cefalexin transport.
However, the L-epimer is also more susceptible to the intestinal
wall peptidases and cannot be detected in serum, whereas the D-
isomer is well absorbed. The drug is marketed as the single D-
epimer
15. i)There was 15% difference in bioavailability of
the enantiomers of Atenolol. It was postulated
that this was a result of an enantioselective
active absorption.
ii)Esomeprazole( Nexium) is more bioavailable than racemic omeprazole( Prilosec).
iii)Greater bioavailability of (-)R-terbutaline compared
to the less active (+)S- enantiomer is due to the result
of
stereoselectivity in first pass metabolism and due to (-
) enantiomer posses increasing membrane
permeability in absorption.
16. Difference in the absorption of enantiomers may also due to
difference in their effect on local blood flow.
(-) Bupivacaine has a longer duration of action than (+) Bupivacaine
following intradermal
injection. This difference in activity is due to vasoconstrictor effects
of the (-) enantiomer reducing
blood flow locally.
The majority of the drugs undergo reversible binding to plasma
proteins.
• In case of chiral drugs, the drug enantiomer- protein complexes
are diastereoisomeric
and individual enantiomers would be expected to exhibit
differences in binding affinity
to the circulating proteins.
• The differences in the binding affinity result in differences between
enantiomers in free
or unbound fraction that is able to distribute into the tissue.
17. The two most important plasma proteins with respect to drug binding are human
serum albumin (HSA) and alpha1-acid glycoprotein (AGP).
a) Generally acidic drugs bind to HSA and basic drugs bind to AGP.
b) Differences between enantiomers in the plasma protein binding may be relatively
small and in some cases less than1%.
Stereoselectivity in plasma protein binding also influences clearance for drugs, total
clearance being proportional to fraction bound.
Differences between enantiomers for plasma protein-binding sites may also result in
pharmacokinetic complications.
Most of the drug undergo reversible binding to plasma proteins.
Types of plasma proteins are-
-Human serum albumin -Weak acid to weak base drugs
-Alpha-1 acid glycoproteins-Basic drugs
-Lipoproteins- Basic lipophilic drugs
-Alpha-1 globulin-Steroids
-Alpha-2 globulin-Vitamins
-Hemoglobin -Phenytoin, pentobarbital, etc
18. Enantiomers display different magnitudes of stereoselectivity between various proteins found in
plasma.
1. R- Propranolol binding to albumin is greater than S- propranolol and S enantiomer binding to
alpha 1 glycoprotein is greater than R- albumin.
2. S- warfarin extensively binds to albumin than R – warfarin thus posses lower volume of
distribution.
3.Levo cetrizin has lesser volume of distribution than its dextro isomer.
R-Propranolol S- Warfarin Levo -cetrizin
19. Enantioselectivity in binding may also vary between HSA and AGP.
R- Propranolol
Highly albumin bound
Less potent
Highly metabolized
Low plasma concentration
S- Propranolol
Highly bound to AGP available as unbound
40 to 100 time more potent
Less metabolized
High plasma concentration
20. (S)-oxazepam hemi succinate binds to HSA with an affinity 40
times than that of R-enantiomer.
Enantioselective protein binding interaction was
reported between warfarin and lorazepam acetate.
Where, R, S- warfarin allosterically increased the
binding of S – Lorazepam acetate, but there was no
effect of them on R enantiomer.
Similarly, S- lorazepam acetate increased the
binding of R,S – Warfarin.
21. Storage mechanisms: The S
enantiomer of adreno receptor
antagonists propranolol and atenolol
undergo selective storage and
secretion.
The uptake of (-)- atenolol in to the
storage granules has been reported to
be 5 fold that of (+)- enantiomer.
Stereoselective distribution may also occur as a result of
interactions with: Tissue uptake transporter:
E.g.: the BBB clearance of the R-enantiomer is four fold
greater than that of
either (S)-or racemic baclofen (Muscle relaxant).
22. Stereoselectivity in metabolism may be associated with the
binding of the substrate to the enzyme, and therefore associated
with the chirality of the enzyme-binding site.
Alternatively, selectivity may be associated with catalysis due to
differential reactivity and/or orientation of potential target groups
with respect to the enzyme catalytic site.
The individual enantiomers of a racemic drug may be
metabolized by different routes to yield different products and
they are metabolized at different rates.
23. The stereoselectivity of the reactions of drug
metabolism may be associated with:
• 1. Substrate stereoselectivity, i.e. the selective
metabolism of one enantiomer compared to the
other in either rate and/or route of metabolism
• 2. Product stereoselectivity, i.e. the preferential
formation of a particular stereoisomer rather than
other possible stereoisomers
• 3. Substrate product specificity, i.e. the selective
metabolism of one enantiomer resulting in the
preferential formation of one of a number of possible
diastereoisomeric products.
Prochiral to chiral
transformations
Chiral to chiral
transformations
Chiral to
diastereo
isomer
transformations
Chiral to achiral
transformations
Chiral
inversions
24. PROCHIRAL TO CHIRAL TRANSFORMATION:
The molecule acquires chirality by metabolism, which
may take place at either a prochiral centre or on an
enantiotopic group bonded to it.
Examples: The antiepileptic drug phenytoin has a
prochiral center at carbon -5 of the hydantoin ring
system and the two phenyl rings are enantiotopic as
indicated by pro-S and pro-R. The major route of
metabolism of phenytoin in both animals and humans
involves aromatic oxidation which in human shows
product stereoselectivity for formation of (S)-4-
hydroxyphenytoin.
CHIRAL TO CHIRAL TRANSFORMATION:
In this type of transformations metabolism take place at a site in the
molecule that does not alter the chirality of the metabolite relative to
that of the drug.
Example: Esmolol is an ultrashort acting relatively cardioselective B-
adrenoreceptor antagonist, is used as a racemate but the
pharmacological activity resides in the enantiomer of the S-
configuration; the R-enantiomer is pharmacologically inactive.
The ester functionality of esmolol is hydrolysed by the enzyme in
blood esterases . The hydrolysis of S-esmolol is faster than that of
the R-enantiomer in the animals whereas in human beings the
hydrolysis of both enantiomers occur at similar rates.
25. CHIRAL TO DIASTEREOISOMER
TRANSFORMATION:
This type of transformation involves the introduction of
an additional stereogenic centre into a chiral molecule .
Such centres may arise by a phase 1 or
functionalization, metabolic reaction at a prochiral
centre or by a phase 2, or conjugation, process by
reaction with a chiral conjugating agent.
Example: Reaction of a first type include reduction of
the prochiral ketone group in warfarin to yield a pair of
diastereoisomeric warfarin alcohols. In both rat and
human, the reduction is substrate selective for (R)-
warfarin and the predominantly formed isomer of the
alcohol has S-configuration at the new centre.
CHIRAL TO ACHIRAL
TRANSFORMATIONS:
In reactions of this type the biotransformation
results in a loss of chirality, the reaction taking place
at the stereogenic centre.
Example: 1,4-dihydropyridine calcium channel
blockers nitrendipine and nilvadipine .
26. CHIRAL INVERSION:
Chiral inversion is a relatively rare metabolic transformation
and involves the conversion of a stereoisomer to its
enantiomer with no other chemical change to the molecule.
Example: The reaction was initially observed in 2-arylpropionic
acid NSAID’s e.g. ibuprofen and since then it has been found to
occur with the chemically related 2-aryloxypropionates, which
are used as herbicides e.g. haloxyfop
27. Renal excretion is the net result of glomerular filteration, active secretion and passive &
active reabsorption.
Since glomerular filteration is a passive process differences between enantiomers
would not be expected.
However, apparent stereoselectivity in renal clearance may arise as a consequence of
stereoselectivity in protein binding.
Active renal tubular secretion is thought to be responsible for the
differential clearance of the enantiomers of number of basic drugs with
stereoselectivities in the range of 1.1 to 3.0
28. Eg : The renal clearance of quinidine is four
times greater than its diastereoisomer quinine.
For those agents that undergo active tubular secretions,
the interactions between the enantiomers may occur in
such a way that their excretions differs as single
enantiomer or as a racemates.
Ex- S- Ofloxacin administration with more of its R –
enantiomer resulted in reduction of renal clearance of S-
enantiomer. Mechanism followed was by competitive
inhibitor of active transport system
29. BIBLOGRAPHY:
a) Smith and William’s introduction to principles of drug
design, second edition, published by John wright,
Pg.no.140-149
b) Burger’s Medicinal Chemistry And Drug Discovery, 6th
edition, pg.no.782-787
c) Thomas L.L and David A Williams, Foye’s Principle of
Medicinal Chemistry, 6th edition, Wolters Kluwer, Chapter
2 pg.24-36