Download Option D8 Drug Action HL

Objectives
 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.
Drug Action
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The effectiveness of a drug is often related to
the chemical structure and polarity of the
substance.
Factors that affect how a drug reacts include:
Chirality
2. Geometrical isomerism
3. Ring strain
4. Polarity
1.
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Chirality Affects Drug
Behavior
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The presence of an asymmetric or
chiral carbon atom in a molecule
results in two different optical
isomers or ENANTIOMERS.
Two different enantiomers can
behave in very different ways in
the body.
The most famous example of this
difference was found in with
thalidomide.
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Thalidomide
 Thalidomide has two
optical isomers, one
of which is a
tranquilizer while the
other is a powerful
teratogen.
Chiral
Carbon
 Originally used to
treat morning sickness
during pregnancy.
 Now used to treat
some symptoms of
Hansen’s disease
(Leprosy).
The high incidence of fetal deformities
has led to increased diligence in
approving drugs for use.
When new drugs are developed now
The pharmacological activity of each
optical isomer must be studied
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separately.
Why chirality matters
Thalidomide and Leprosy
Thalidomide is used in the
treatment of Erythema nodosum
leprosum (ENL), a painful
inflammatory dermatologic
reaction of leprosy
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Geometric Isomers Differ in
Behavior
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Geometric isomerism occurs in both organic and
inorganic compounds.
Diaminechloroplatnium (II) is an inorganic complex
that as been used to treat certain types of
ovarian and testicular cancers.
Diaminechloroplatnium (II) exists in both cis and
trans isomers.
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Cis and Transplatin
The structures of the cis and trans
forms are shown below:
Cis-platin is an effective anticancer drug, while
Trans-platin is not effective at all.
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Cisplatin as an Anti-cancer Drug
 Cisplatin can diffuse through
a cancer cell membrane.
 In the cell it exchanges a
chloride ion for a water
molecule forming a complex
ion.
 This complex ion binds to
the cancer cell DNA
preventing it from replicating
correctly.
The cis-platin form is just the
right size to bind to the guanine
bases on the DNA.
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DNA without
CIS-platin
DNA with
CIS-platin
Ring Strain
The action of beta lactams in antibacterial drugs
such as the penicillins is an example of the effect
of ring strain as a drug mechanism.
The general structure of penicillin
The four member ring of the betal lactam contains a carbon that is sp2
hybridized and a nitrogen atom and 2 carbon atoms that are sp3
hybridized. The restrictions of the ring prevent the atoms from
assuming the normal bond angles of 120o and 109.5o respectively.
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Ring Strain and Drug Activity
The amide group in the
ring is more reactive
due to the strained ring.
The structure of the
beta lactam is similar to
the structures of
cysteine and valine.
The beta lactam binds
to the enzyme that
synthesizes the cell wall
in bacteria blocking its
action.
As a result the bacteria
rupture and break and
cannot reproduce.
Note the similarities in structure
to the beta lactam.
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Polarity
Polarity and Drug Behavior
 The difference in polarity
between molecules affects
their behavior in the body.
 The polarity of a molecule
affects:
1. its ability to dissolve in
lipids
2. its ability to pass
through the lipid
membranes
3. the degree to which it
may bind to an active
site on an enzyme or
protein.
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Polarity: Morphine and Heroin
Heroin is much more potent
than morphine (and more
addictive).
The –OH groups on morphine
are more polar than the
ethanoate ester groups on
heroin.
Heroin is more lipid soluble in
lipids.
It can more readily penetrate
the blood-brain barrier and it is
absorbed in higher
concentrations in the brain.
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 MORPHINE
 HEROINE
 -OH polar groups
 Ester less-polar groups
 Not lipid soluble
 Lipid soluble
 Hard to get in brain
 Easy to get in brain
Modifying polarity
Amine + HCl => hydrochloride salt (ionic, more
soluble)
Prozac
Modifying polarity
Carb. Acid + NaOH => Sodium salt (ionic, more
soluble)
Aspirin
Thalidomide
 Read the three articles on Thalidomide in class today. Write a 2-3
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page integrated paper in which you discuss adequately the following;
1.
What is thalidomide? When did the drug first appear on the
market? What was its original purpose
2.
What was there about thalidomide that makes the drug
hazardous? Explain and describe the tragic results that resulted
from thalidomide use.
3.
Thalidomide has two enantiomers. Explain the differences.
Are both isomers teratogens?
4.
What kinds of problems with drug regulations allowed
thalidomide to be marketed in Europe but not in the USA?
5.
What kinds of testing should be required before a drug is
approved for use? In what respect is animal testing important in
this respect?
6.
Recently thalidomide has been used to treat other conditions.
What are these conditions? What are the benefits and potential
risks
Drug Design
Part 2
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What is Combinatorial Chemistry?
 Is an approach that provides efficient synthesis of a
large collection of molecules
 Screening of libraries of related compounds to isolate
the molecule of desirable property
 Used in both academia and industries to generate
huge libraries of compounds that have important
biological properties
Combinatorial Chemistry
 Drug companies have developed libraries of
compounds which have been screened for drug
activity.
 With a given core molecule or pharmacore, and a
large number of substituents, researchers use
computers to enumerate a large number of structural
possibilities.
 This virtual library may consist of thousands, or even
millions of 'virtual' compounds.
 Researchers select a subset of the 'virtual library' for
actual synthesis, based upon various calculations and
criteria.
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Combinatorial Chemistry
 An example of a
pharmacore and
a reactant
system.
 By examining
multiple
possibilities
pharmaceutical
chemists can
evaluate the
medical efficacy
of various
molecules for
medicinal value.
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Combinatorial Chemistry
 The process was originally developed for polypeptide
synthesis with amino acids.
 The starting material or pharmacore is covalently
bonded to small polystyrene resin beads.
 The beads are reacted with various groups in
successive steps.
 The beads are separated from the reaction mixture and
then undergo preliminary screening for drug activity.
 This is usually done by measuring how the substance
affects enzymes or how it may bind to receptor cells.
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Solid Phase Library
In 1991s, Houghten & Lam: synthesis of a huge peptide library
20 amino acids
Solid-phase synthesis
202 = 400 dipeptides
DNA: fully automatic (solution)
peptide
203 = 8000 tripeptides
204 = 160,000 tetrapeptides
carbohydrate
small molecule (drug-like)
ln 1992, Jon Ellman: synthesis of non-peptide drug-like molecules by
solid phase synthesis
Combinatorial Chemistry
A combinatorial scheme for amino acids
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Parallel Synthesis
 Alternative to combinatorial approach,
 Solid state organic.
 Preparation of a highly reactive intermediate.
 Preparation of individual compounds simultaneously
with various reagents in separate microcells without
mixing intermediates during synthesis.
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Parallel synthesis
 On a teflon reaction block
 Large number of wells
 Add different parts at each step
 Common conditions
12-well reaction block
Add Scaffold to each well
S
S
S
S
S
S
S
S
S
S
S
S
Wells after Addition of first
reagent
SA
SB
SC
SD
SA
SB
SC
SD
SA
SB
SC
SD
There are now twelve different
products
SA1
SB1
SC1
SD1
SA2
SB2
SC2
SD2
SA3
SB3
SC3
SD3
Drug Polarity Modifications
 Many compounds that are of pharmacological importance
are large complex organic molecules that are not very polar
 They are largely insoluble in water. Their ionic salts, either
as sodium salts or hydrochloride salts are used to make
them more soluble.
Aspirin or acetyl
salicyclic acid is
converted to the
sodium salt.
Sertraline is an amine
compound that is
converted to a
hydrochloride salt to
make it more soluble.
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Chiral Auxillaries
 Traditional synthesis of optically active compounds
results in a racemic mixture with equal amounts of
each enantiomer.
 Only one of the enantiomers has pharmacological
value. (i.e. thalidomide).
 Separating enantiomers from racemic mixtures is often
difficult and complicated.
 The use of chiral auxilliaries makes it possible to
synthesize only one of the two enantiomers.
 A chiral auxilliary is a chiral molecule that is attached
to the starting material during a synthesis that creates
the appropriate stereo-chemical environment so that
only one enantiomer is produced.
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Asymmetric Synthesis
Synthesis of One Enantiomer using a Chiral Auxiliary
O
O
O
chemical steps
OH
NH
2
OH
Put auxiliary on
OH
NH
2
Bothhandedforms of product
(racemic mixture; 1:1mixtureof enantiomers)
O
O
chemical steps
O
takeauxiliary off
OH
NH
2
NH
2
O
[
HN
Chiral Auxiliary
:
O
]
Synthesis with Chiral Auxilliaries
A chiral auxiliary is a molecule that is temporarily incorporated into
an organic synthesis. Its asymmetry allows the formation of a
chiral intermediate followed by selective formation of one of two
stereoisomers depending on the reagent and/or reaction
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conditions.
Taxol
 The anti-cancer drug TAXOL is found in the Pacific
Yew tree, but there is not a sufficient supply to meet
demand.
 SinceTaxol is a very chiral molecule, one possibility
is to make it synthetically.
 The potential synthesis is very complicated and
would require using several chiral auxilliaries..
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Computer aided drug design