Transcript Slide 1

Drug Action and
Design
IB Chemistry Option D: Drugs and
Medicines
Larry J. Scheffler
Lincoln High School
Drug Action
• 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:
1.
2.
3.
4.
Chirality
Geometrical isomerism
Ring strain
Polarity
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Chirality Affects Drug
Behavior
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The presence of an asymmetric or chiral
carbon atom in a molecule resultsin 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
separately.
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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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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 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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Drug Design
Part 2
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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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Combinatorial Chemistry
A combinatorial scheme for amino acids
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Parallel Synthesis
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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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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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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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