Transcript Geometric isomers

By
Lisa Grossman
Max Krakauer
Sarah Theobald
With revisions by Ms. Smith
D.8.1 Describe the importance of geometrical
isomerism in drug action
D.8.2 Discuss the importance of chirality in
drug action
D.8.3 Explain the importance of beta-lactam
ring action of penicillin
D.8.4 explain the increased potency of
diamorphine (heroin) compared to morphine:
Review - What Are Stereoisomers?
Stereoisomers
► two isomers
► same molecular formula
► same structural formulas
but
► different spatial arrangements of atoms
The Two Types of Stereoisomers
►Geometric
isomers
►Optical isomers
Geometric Isomers
Geometric isomers (or cis-trans isomers)
are molecules with a double bond that
form cis and trans isomers.
► note
that square planar molecules can
also display geometric isomerism
cis and trans refers to the orientation of
functional groups within a molecule
Geometric Isomers
Cis (on the same side)
Trans (across/opposite sides)
Cis-2-butene
Trans-2-butene
Molecular Formula- C4H8
Structural Formula- CH3CHCHCH3
Molecular Formula- C4H8
Structural Formula- CH3CHCHCH3
Different sides
Same side
Differences in
Physical and Chemical Properties
for Geometric Isomers
► undergo
different chemical reactions.
► Stability (trans are usually more stable)
► Polarity
► Boiling/Melting point
► Solubility
Geometric Isomers and Drugs
Because geometric isomers have different
chemical and physical properties, they act
differently as drugs in our bodies as well.
Example :
•cis-platin used for chemotherapy - it can
enter cancer cells and interact with DNA
•Trans- platin - not active
Optical Isomers
Optical isomers
► have a chiral center
► non-super
imposable mirror
images
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 rotating
enantiomer.
Racemic mixture: A mixture of 50% left rotating and 50%
right rotating optical isomers
How can you tell
if a molecule is chiral?
Optical isomers will always have a chiral
(central) carbon with four single bonds each
attached to a different substituent.
Example: Which molecule is not chiral?
A. CH3CHClOH
B. CH3CHCOOHNH2
C. BrCH2COOH
Using a Polarimeter
A polarimeter is a machine that can tell
what optical isomer a substance contains by
giving a rotational quantity in degrees
 If
the rotational value is positive the optical
isomer is right handed.
 If the rotational value is negative the optical
isomer is left handed.
Using a Polarimeter
If a molecule rotates at +24 degrees, is it right
handed or left handed?
Right
If a molecule rotates at -24 degrees, is it right
handed or left handed?
Left
If a molecule rotates at 0 degrees, is it right handed
or left handed?
Both-it is 50% Right and 50% Left
(This is called a racemic mixture.)
Optical Isomers and Drugs
► Optical
Isomers interact differently in our
bodies because our bodies themselves are
chiral.
► Thus
important to make sure you have the
right optical isomers in your drugs.
 Thalidomide tragedy- one enantiomer stops
morning sickness in pregnant women. The drug
was sold as a racemic mixture to reduce costs.
However, it was later discovered that the other
enantiomer causes severe birth defects.
► Many
drugs are still sold as a racemic mixture
to reduce costs, including advil, motrin, and
vitamin E.
D.8.3 Explain the importance of beta-lactam
ring action of penicillin
Penicillin
• R group
• carboxylic acid group
• Beta-lactam ring
• heteroatomic four-membered ring
• strained ring (90° vs 109.5°) is very
reactive
• open ring binds with enzyme needed for
synthesis of linkages in bacterial cell walls
• so… bacteria burst
D.8.4 explain the increased potency of
diamorphine (heroin) compared to morphine:
Heroin
•
two polar hydroxyl groups replaced by two less
polar ester groups
• more fat soluble
• more readily absorbed into the non-polar
environment of the central nervous system and
the brain
D.9.1 Discuss the use of a compound library in
drug design.
D.9.2 Explain the use of combinatorial and
parallel chemistry to synthesize new drugs
D.9.3 Describe how computers are used in
drug design
D.9.4 Discuss how the polarity of a molecule
can be modified to increase its aqueous
solubility and how this facilitates its
distribution around the body
D.9.5 Describe the use of chiral auxiliaries to
form the desired enantiomer
Synthesis of New Drugs

often starts with ‘lead’ compound pharmacologically active

uses organic chemistry to make small
changes to the drug’s structure to produce a
more effective drug
 more potent, fewer side effects

result is a compound library – a collection
of related compounds that can be tested for
their pharmacological activity
Combinatorial Chemistry
(Combi-Chem)

a way of synthesizing and testing potential new drugs that
reduces time and costs

a set of reactants are reacted in all possible combinations

resulting compounds are cataloged by computers, called a
compound (or combinatorial) library

library is tested in the laboratory en masse (all at once)
for pharmacological activity

large libraries increase the chances of finding better drugs
Combinatorial Chemistry
(Combi-Chem)

much of the process is streamlined with technology /
computerization /

Robotics can be used to carry out identical chemical
processes simultaneously
 Known as “parallel synthesis”
Example of Synthesis in Combi-Chem:
Synthesizing Polypeptides
► amino
acids (peptides) are the building
blocks of protein molecules
► amino acids are combined to make
dipeptides in condensation reactions.
Peptide linkage
water
Example: Synthesizing Polypeptides
Because amino acids (peptides) contain both a
carboxylic acid group and an amino group, two
amino acids can be combined in four different ways
to make dipeptides.
Peptide
Peptide
Peptide
Peptide
A-Peptide
A-Peptide
B-Peptide
B-Peptide
A
B
A
B
Example: Synthesizing Polypeptides
A simple two stage combi-chem reaction
is used to make dipeptides.
Starts with a linking group attached to a
plastic bead.
Plastic bead
H
C
Cl
H
Example: Synthesizing Polypeptides
Stage one: the carboxylic acid group from
an amino acid reacts with the Cl of the
linking group… the amino acid now has its
amine group ready to react
Plastic bead
H
C
Cl
Plastic bead
H
+
amino
acid A
=
H
C
H
amino acid A
+ HCl
Example: Synthesizing Polypeptides
Stage two: Product of previous reaction is
washed and then reacted with aa B, forming a
peptide bond… making a dipeptide.
Plastic bead
Plastic bead
H
C
H
amino acid A
+
amino
acid B
H
C
H
+ H2O
amino acid A
dipeptide
Later, the plastic bead-CH2 is removed amino acid B
to leave the dipeptide.
Example: Synthesizing Polypeptides
► Next
step?
► Continue reactions to make polypeptides or
► Remove the plastic bead-CH2 to leave the
dipeptide.
Plastic bead
H
C
H
amino acid A
dipeptide
amino acid B
Example: Synthesizing Polypeptides
A typical two stage reaction in four containers
1
Stage 1
Stage 2
2
3
PB + aaA
PB + aaA
PB + aaB
PBaaA + aaA
PBaaA + aaB
PBaaB + aaA
4
PB + aaB
PBaaB + aaB
RESULT
A-A
A-B
B-A
B-B
Example: Synthesizing Polypeptides
►a
combination of two amino acids
makes 4 (22) dipeptides
► Using three amino acids,
makes 9 (32) dipeptides
► Using
(two stages)
(two stages)
three amino acids
(three stages)
makes 27 (33) tripeptides
► Using three amino acids
(four stages)
makes 81 (34) tetrapeptides
Example: Synthesizing Polypeptides
So the general formula for the total number of
possible polypeptides formed is…
Number of amino acids = p
Number of stages in the reaction = s
Number of polypeptides formed
=
S
p
Synthesizing other molecules ????
Scientists quickly realized that this
methodology could be applied to other
synthesis reactions.
Organic heterocyclics are often used as
starting materials for potential drugs… with
the addition of different branches often
leading to new and better drugs.
How can Computers Help?
mode of drug action in the body usu involves
interaction with biological molecules
•
•
enzymes
pharmacophore (receptor site)
molecular modeling software
•
more powerful, cheaper, more available
•
able to convert 2D structure into 3D structure
allows ‘virtual testing’ of drug with receptor site / enzyme
•
A drug may be an Inhibitor molecule (ligand)
•
interfer with active site of an enzyme…
Polarity of Molecules
In
general, a drug that is altered to contain
an ionic group is more soluble in aqueous
solutions (like body fluids)… and therefore
more effective.
However
- some drugs that are fat soluble
are more effective… if their target is the
central nervous system… the brain… fatty cell
membranes of nerve cells…
 mescaline more potent than psylocybin
 heroin more potent than morphine
Polarity of Molecules – Case in Point
Aspirin

salicylic acid (2-hydroxybenzoic acid)
•
•
•
•
fever reducer, pain killer
strong acid
unpleasant to take orally
damaging to membranes
lining mouth, esophagus, stomach
Aspirin

sodium salicylate
• fever reducer, pain killer
• soluble ionic salt of salicylic acid
• still bitter taste
• still damaging to stomach
when it reverts to salicylic acid
Aspirin

acetyl salicylic acid (ASA)
• fever reducer, pain killer
•
•
•
•
acetate (ethanoate) ester of salicylic acid
relatively tasteless
only weakly acidic
relatively insoluble
Aspirin

acetyl salicylic acid (ASA)
•
called a
prodrug
►Reacts
with water
in basic environment of
small intestines
to form the active salicylic acid molecule.
• also available as the sodium salt of ASA
•
more soluble… more effective
Synthesis of Drugs and Chirality
How drugs can be synthesized
► Derivation
from natural sources
► Modification of natural substances
► Laboratory synthesis
Usually only one enantiomer is found in nature, so
naturally derived drugs usually contain an excess
of one enantiomers while laboratory drugs are
occasionally racemic mixtures
Chiral Auxiliaries
 New:
stereospecific synthesis or
asymmetric synthesis
Stereospecific synthesis involves the use of
chiral auxiliaries to make only one
enantiomer of a molecule
What is a Chiral Auxiliary?
►
molecule that attaches itself chemically to the
chiral molecule being synthesized

creates conditions which cause the drug synthesis
to follow a certain stereospecific path – producing
only one type of enantiomer

auxilary is removed or replaced to leave the
desired enantiomer.
If you’re still confused, here’s a diagram
The top reaction is unmodified… the bottom reaction uses a chiral modifier…
Notice the different yields…. Much higher in bottom reaction.